Osteogenesis Imperfecta Type V

Mendelian MONDO:0012591 Pathograph 3 Osteogenesis imperfecta

Osteogenesis imperfecta type V is a distinct form of OI caused by a specific heterozygous mutation in IFITM5 (interferon-induced transmembrane protein 5), not by collagen gene mutations. It is characterized by moderate severity, hyperplastic callus formation after fractures, calcification of the interosseous membrane of the forearm causing limitation of pronation/supination, and a distinctive mesh-like (reticular) lamellation pattern on bone histology. Scleral hue is normal and dentinogenesis imperfecta is absent.

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1
Inheritance
2
Pathophys.
10
Phenotypes
3
Pathograph
1
Genes
3
Treatments
7
References
2
Deep Research
👪

Inheritance

1
Autosomal Dominant
Autosomal dominant inheritance. A single recurrent mutation in IFITM5 (c.-14C>T in the 5'UTR) accounts for all cases, creating a new upstream start codon that adds 5 amino acids to the protein.
Show evidence (1 reference)
PMID:10976985 SUPPORT Human Clinical
"The family history was positive for OI in 3 patients, with an autosomal dominant pattern of inheritance."
The original description of OI type V established autosomal dominant inheritance based on family histories.
⚙

Pathophysiology

2
IFITM5 Gain-of-Function
The c.-14C>T mutation creates an upstream start codon, producing an IFITM5 protein with 5 additional N-terminal amino acids. This altered protein disrupts normal bone mineralization and matrix organization, leading to the characteristic histological and clinical features. IFITM5 (BRIL) is an osteoblast-specific protein involved in mineralization.
Osteoblast link
Bone Mineralization link Osteoblast Differentiation link
Downstream
ERK/SOX9-Dependent Osteoprogenitor Differentiation Defect Mutant IFITM5 activates ERK signaling and downstream SOX9, altering osteo-chondroprogenitor differentiation.
Show evidence (1 reference)
PMID:22863190 SUPPORT In Vitro
"Transfection of wild-type and mutant IFITM5 constructs revealed that the mutation added five amino acids (Met-Ala-Leu-Glu-Pro) to the N terminus of IFITM5. Given that IFITM5 expression and protein localization is restricted to the skeletal tissue and IFITM5 involvement in bone formation, we..."
Demonstrates the mutation produces an extended N-terminal protein and establishes IFITM5 as a bone-specific protein involved in bone formation.
ERK/SOX9-Dependent Osteoprogenitor Differentiation Defect
Conditional mutant IFITM5 expression in osteo-chondroprogenitor and chondrogenic cells activates ERK signaling and downstream SOX9 protein, expands periosteal skeletal progenitor populations, decreases differentiation into osteoblasts, and produces cartilage overgrowth with abnormal growth-plate architecture.
Osteo-chondroprogenitor-like mesenchymal stem cell link Osteoblast link Hypertrophic chondrocyte-like cell link
ERK1 and ERK2 cascade link ↑ INCREASED Osteoblast differentiation link ↓ DECREASED Chondrocyte differentiation link ⚠ ABNORMAL Endochondral ossification link ⚠ ABNORMAL
Downstream
Hyperplastic Callus Formation Abnormal osteo-chondroprogenitor differentiation provides a mechanistic route to the ectopic and exuberant bone-forming phenotype of OI type V.
Show evidence (2 references)
PMID:38885336 SUPPORT Model Organism
"Expression of the mutant Ifitm5 in osteo-chondroprogenitor or chondrogenic cells resulted in low bone mass and growth retardation."
The conditional mouse model localizes mutant IFITM5 effects to osteo-chondroprogenitor and chondrogenic stages rather than mature osteoblasts alone.
PMID:38885336 SUPPORT Model Organism
"mutant IFITM5 disrupted early skeletal homeostasis in part by activating ERK signaling and downstream SOX9 protein, and inhibition of these pathways partially rescued the phenotype in mutant animals."
This directly supports the ERK/SOX9 signaling component requested by the review and links it to rescue by pathway inhibition.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Osteogenesis Imperfecta Type V Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

10
Eye 1
Blue Sclerae EXCLUDED Blue sclerae (HP:0000592)
Show evidence (1 reference)
PMID:23804581 SUPPORT Human Clinical
"Blue sclera and dentinogenesis imperfecta were not evident in any patient."
In this mutation-confirmed cohort, blue sclerae were absent in all 16 patients.
Head and Neck 2
Hypodontia FREQUENT Hypodontia (HP:0000668)
Show evidence (1 reference)
PMID:23804581 SUPPORT Human Clinical
"However, hypodontia in the permanent teeth, ectopic eruption, and short roots in molars were additionally observed in 11 patients."
Hypodontia was reported in 11 of 16 mutation-confirmed patients (69%), which supports a FREQUENT classification.
Dentinogenesis Imperfecta EXCLUDED Dentinogenesis imperfecta (HP:0000703)
Show evidence (1 reference)
PMID:30593885 SUPPORT Human Clinical
"None of the individuals had dentinogenesis imperfecta."
This dedicated dental cohort confirms that dentinogenesis imperfecta is absent in OI type V.
Limbs 2
Radial Head Dislocation VERY_FREQUENT Dislocated radial head (HP:0003083)
Show evidence (1 reference)
PMID:23408678 SUPPORT Human Clinical
"Thirteen had calcification of interosseous membranes, 14 had radial head dislocations, 10 had HPC, 9 had long bone bowing, 11 could ambulate without assistance, and 1 had mild unilateral mixed hearing loss."
In this cohort, radial head dislocation occurred in 14 of 17 individuals (82%), which supports a VERY_FREQUENT classification.
Bowing of the Long Bones FREQUENT Bowing of the long bones (HP:0006487)
Show evidence (1 reference)
PMID:23408678 SUPPORT Human Clinical
"Thirteen had calcification of interosseous membranes, 14 had radial head dislocations, 10 had HPC, 9 had long bone bowing, 11 could ambulate without assistance, and 1 had mild unilateral mixed hearing loss."
Long-bone bowing was reported in 9 of 17 individuals (53%), which falls in the FREQUENT range.
Musculoskeletal 2
Hyperplastic Callus Formation FREQUENT Hyperplastic callus formation (HP:0030268)
Show evidence (1 reference)
PMID:23804581 SUPPORT Human Clinical
"Hyperplastic callus was detected in 75% of patients and was commonly encountered at the femur."
This mutation-confirmed cohort quantifies hyperplastic callus formation as a frequent feature of OI type V (75%, within the FREQUENT 30-79% band).
Recurrent Fractures Recurrent fractures (HP:0002757)
Show evidence (1 reference)
PMID:10976985 SUPPORT Human Clinical
"These children had a history of moderate to severe increased fragility of long bones and vertebral bodies."
The original OI type V description documented moderate to severe bone fragility affecting long bones and vertebral bodies.
Other 3
Limited Forearm Pronation/Supination Limited pronation/supination of forearm (HP:0006394)
Show evidence (1 reference)
PMID:10976985 SUPPORT Human Clinical
"All type V patients had limitations in the range of pronation/supination in one or both forearms, associated with a radiologically apparent calcification of the interosseous membrane."
The original description of OI type V showed that all patients had interosseous membrane calcification limiting forearm rotation.
Dense Metaphyseal Bands Dense metaphyseal bands (HP:0100959)
Show evidence (2 references)
PMID:10976985 SUPPORT Human Clinical
"A radiodense metaphyseal band immediately adjacent to the growth plate was a constant feature in growing patients."
The original clinical description identifies dense metaphyseal bands as a defining radiographic feature of OI type V in growing children.
PMID:20872883 SUPPORT Human Clinical
"We show the evolution of metaphyseal abnormalities from a rickets-like appearance to the classically described dense metaphyseal bands."
This infant case report independently confirms dense metaphyseal bands as part of the OI type V radiographic phenotype.
Ectopic Ossification OCCASIONAL Ectopic ossification (HP:0011986)
Show evidence (2 references)
PMID:23804581 SUPPORT Human Clinical
"Heterotopic ossification in the muscles and tendon insertion sites were noted in four patients, which resulted in bony ankylosis or contracture of joints."
Ectopic ossification was documented in 4 of 16 patients (25%), supporting an OCCASIONAL classification and showing clinical consequences on joint mobility.
PMID:31099171 SUPPORT Human Clinical
"CONCLUSION: Ossification of the origin and attachment of muscles seems to be part of the phenotype in patients with OI type V."
This independent case report supports heterotopic ossification as part of the OI type V phenotype.
🧬

Genetic Associations

1
IFITM5 c.-14C>T Mutation (Causative)
Show evidence (1 reference)
PMID:22863190 SUPPORT Human Clinical
"Using linkage analysis in a four-generation family and whole-exome sequencing, we identified a heterozygous mutation of c.-14C>T in the 5'-untranslated region of a gene encoding interferon-induced transmembrane protein 5 (IFITM5). It completely cosegregated with the disease in three families and..."
Landmark paper identifying the single recurrent IFITM5 c.-14C>T mutation as the cause of all OI type V cases.
💊

Treatments

3
Bisphosphonate Therapy
Action: Bisphosphonate therapy Ontology label: bisphosphonate agent therapy MAXO:0000954
Bisphosphonates may reduce fracture frequency, though hyperplastic callus can still occur.
Show evidence (1 reference)
PMID:32797291 SUPPORT Other
"Management of patients with OI involves medical treatment by bisphosphonates as the most promising therapy to inhibit bone resorption and thereby facilitate bone formation."
Review of OI therapeutic options identifies bisphosphonates as the primary medical treatment to reduce bone resorption and promote bone formation.
Surgical Management
Action: Orthopedic surgery Ontology label: surgical procedure MAXO:0000004
Orthopedic surgery for fractures and deformities should be planned cautiously in patients with exuberant hyperplastic callus; distinguish OI type V callus from osteosarcoma before aggressive oncologic procedures.
Show evidence (2 references)
PMID:32797291 SUPPORT Other
"Surgical treatment ensures pain reduction and healing without an increase of deformities."
Review identifies surgical treatment as an important component of OI management for pain reduction and healing.
DOI:10.3389/fendo.2021.622674 SUPPORT Human Clinical
"Although the patient was at a predisposing age for osteosarcoma, diagnosis and treatment should be based on the medical history of the patient, imaging,and genetic testing, and sometimes even time-consuming retrospective observation."
Supports caution before amputation or other aggressive oncologic procedures when an OI type V hyperplastic callus mimics osteosarcoma.
Interosseous Membrane Excision
Action: Surgical excision Ontology label: surgical procedure MAXO:0000004
Surgical removal of calcified interosseous membrane to restore forearm rotation in selected cases.
{ }

Source YAML

click to show 
name: Osteogenesis Imperfecta Type V
creation_date: '2026-02-06T03:25:37Z'
updated_date: '2026-04-19T07:28:20Z'
category: Mendelian
description: >
  Osteogenesis imperfecta type V is a distinct form of OI caused by a specific
  heterozygous mutation in IFITM5 (interferon-induced transmembrane protein 5),
  not by collagen gene mutations. It is characterized by moderate severity,
  hyperplastic callus formation after fractures, calcification of the interosseous
  membrane of the forearm causing limitation of pronation/supination, and a
  distinctive mesh-like (reticular) lamellation pattern on bone histology.
  Scleral hue is normal and dentinogenesis imperfecta is absent.
disease_term:
  preferred_term: Osteogenesis imperfecta type V
  term:
    id: MONDO:0012591
    label: osteogenesis imperfecta type 5
parents:
- Osteogenesis imperfecta
inheritance:
- name: Autosomal Dominant
  description: >
    Autosomal dominant inheritance. A single recurrent mutation in IFITM5
    (c.-14C>T in the 5'UTR) accounts for all cases, creating a new upstream
    start codon that adds 5 amino acids to the protein.
  evidence:
  - reference: PMID:10976985
    reference_title: "Type V osteogenesis imperfecta: a new form of brittle bone disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The family history was positive for OI in 3 patients, with an autosomal
      dominant pattern of inheritance.
    explanation: >-
      The original description of OI type V established autosomal dominant
      inheritance based on family histories.
prevalence:
- population: Chinese cohort of 298 osteogenesis imperfecta probands
  percentage: 5.03%
  notes: >-
    In a large contemporary Chinese OI cohort, type V accounted for about 1 in
    20 probands, consistent with its status as an uncommon but recurrent
    non-collagen OI subtype.
  evidence:
  - reference: PMID:40282376
    reference_title: "The Spectra of Pathogenic Variants and Phenotypes in a Chinese Cohort of 298 Families with Osteogenesis Imperfecta"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our OI cohort included 71 type I (23.83%), 122 type III (40.94%), 90 type IV (30.20%), and 15 type V (5.03%) probands."
    explanation: This large genotype-phenotype cohort directly reports that OI type V represented 5.03% of 298 OI probands.
pathophysiology:
- name: IFITM5 Gain-of-Function
  description: >
    The c.-14C>T mutation creates an upstream start codon, producing an
    IFITM5 protein with 5 additional N-terminal amino acids. This altered
    protein disrupts normal bone mineralization and matrix organization,
    leading to the characteristic histological and clinical features. IFITM5
    (BRIL) is an osteoblast-specific protein involved in mineralization.
  cell_types:
  - preferred_term: Osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: Bone Mineralization
    term:
      id: GO:0030282
      label: bone mineralization
  - preferred_term: Osteoblast Differentiation
    term:
      id: GO:0001649
      label: osteoblast differentiation
  evidence:
  - reference: PMID:22863190
    reference_title: "A single recurrent mutation in the 5'-UTR of IFITM5 causes osteogenesis imperfecta type V."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Transfection of wild-type and mutant IFITM5 constructs revealed that the
      mutation added five amino acids (Met-Ala-Leu-Glu-Pro) to the N terminus of
      IFITM5. Given that IFITM5 expression and protein localization is restricted
      to the skeletal tissue and IFITM5 involvement in bone formation, we conclude
      that this recurrent mutation would have a specific effect on IFITM5 function.
    explanation: >-
      Demonstrates the mutation produces an extended N-terminal protein and
      establishes IFITM5 as a bone-specific protein involved in bone formation.
  downstream:
  - target: ERK/SOX9-Dependent Osteoprogenitor Differentiation Defect
    description: >
      Mutant IFITM5 activates ERK signaling and downstream SOX9, altering
      osteo-chondroprogenitor differentiation.
    causal_link_type: DIRECT
- name: ERK/SOX9-Dependent Osteoprogenitor Differentiation Defect
  description: >
    Conditional mutant IFITM5 expression in osteo-chondroprogenitor and
    chondrogenic cells activates ERK signaling and downstream SOX9 protein,
    expands periosteal skeletal progenitor populations, decreases
    differentiation into osteoblasts, and produces cartilage overgrowth with
    abnormal growth-plate architecture.
  cell_types:
  - preferred_term: Osteo-chondroprogenitor-like mesenchymal stem cell
    term:
      id: CL:0000134
      label: mesenchymal stem cell
  - preferred_term: Osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: Hypertrophic chondrocyte-like cell
    term:
      id: CL:0000743
      label: hypertrophic chondrocyte
  biological_processes:
  - preferred_term: ERK1 and ERK2 cascade
    term:
      id: GO:0070371
      label: ERK1 and ERK2 cascade
    modifier: INCREASED
  - preferred_term: Osteoblast differentiation
    term:
      id: GO:0001649
      label: osteoblast differentiation
    modifier: DECREASED
  - preferred_term: Chondrocyte differentiation
    term:
      id: GO:0002062
      label: chondrocyte differentiation
    modifier: ABNORMAL
  - preferred_term: Endochondral ossification
    term:
      id: GO:0001958
      label: endochondral ossification
    modifier: ABNORMAL
  evidence:
  - reference: PMID:38885336
    reference_title: The IFITM5 mutation in osteogenesis imperfecta type V is associated with an ERK/SOX9-dependent osteoprogenitor differentiation defect.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Expression of the mutant Ifitm5 in osteo-chondroprogenitor or chondrogenic cells resulted in low bone mass and growth retardation.
    explanation: >-
      The conditional mouse model localizes mutant IFITM5 effects to
      osteo-chondroprogenitor and chondrogenic stages rather than mature
      osteoblasts alone.
  - reference: PMID:38885336
    reference_title: The IFITM5 mutation in osteogenesis imperfecta type V is associated with an ERK/SOX9-dependent osteoprogenitor differentiation defect.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      mutant IFITM5 disrupted early skeletal homeostasis in part by activating ERK signaling and downstream SOX9 protein, and inhibition of these pathways partially rescued the phenotype in mutant animals.
    explanation: >-
      This directly supports the ERK/SOX9 signaling component requested by the
      review and links it to rescue by pathway inhibition.
  downstream:
  - target: Hyperplastic Callus Formation
    description: >
      Abnormal osteo-chondroprogenitor differentiation provides a mechanistic
      route to the ectopic and exuberant bone-forming phenotype of OI type V.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
genetic:
- name: IFITM5 c.-14C>T Mutation
  association: Causative
  notes: >
    A single recurrent mutation (c.-14C>T) in the 5'UTR of IFITM5 causes all
    cases of OI type V. This creates an upstream AUG start codon, resulting
    in an extended protein with 5 additional N-terminal amino acids (MALEP).
    This is a gain-of-function mechanism distinct from the collagen defects
    in classical OI.
  evidence:
  - reference: PMID:22863190
    reference_title: "A single recurrent mutation in the 5'-UTR of IFITM5 causes osteogenesis imperfecta type V."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using linkage analysis in a four-generation family and whole-exome sequencing,
      we identified a heterozygous mutation of c.-14C>T in the 5'-untranslated region
      of a gene encoding interferon-induced transmembrane protein 5 (IFITM5). It
      completely cosegregated with the disease in three families and occurred de novo
      in five simplex individuals.
    explanation: >-
      Landmark paper identifying the single recurrent IFITM5 c.-14C>T mutation as
      the cause of all OI type V cases.
phenotypes:
- name: Hyperplastic Callus Formation
  description: >
    Exuberant callus formation after fracture is a characteristic complication
    of osteogenesis imperfecta type V.
  phenotype_term:
    preferred_term: Hyperplastic callus formation
    term:
      id: HP:0030268
      label: Hyperplastic callus formation
  frequency: FREQUENT
  evidence:
  - reference: PMID:23804581
    reference_title: "Osteogenesis imperfecta type V: clinical and radiographic manifestations in mutation confirmed patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hyperplastic callus was detected in 75% of patients and was commonly
      encountered at the femur.
    explanation: >-
      This mutation-confirmed cohort quantifies hyperplastic callus formation as
      a frequent feature of OI type V (75%, within the FREQUENT 30-79% band).
- name: Limited Forearm Pronation/Supination
  description: >
    Forearm rotation is limited because of calcification of the interosseous
    membrane between the radius and ulna.
  phenotype_term:
    preferred_term: Limited pronation/supination of forearm
    term:
      id: HP:0006394
      label: Limited pronation/supination of forearm
  evidence:
  - reference: PMID:10976985
    reference_title: "Type V osteogenesis imperfecta: a new form of brittle bone disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All type V patients had limitations in the range of pronation/supination
      in one or both forearms, associated with a radiologically apparent
      calcification of the interosseous membrane.
    explanation: >-
      The original description of OI type V showed that all patients had
      interosseous membrane calcification limiting forearm rotation.
- name: Radial Head Dislocation
  description: >
    Radial head dislocation is a very common forearm abnormality in
    mutation-confirmed OI type V cohorts.
  phenotype_term:
    preferred_term: Radial head dislocation
    term:
      id: HP:0003083
      label: Dislocated radial head
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:23408678
    reference_title: "Phenotypic variability of osteogenesis imperfecta type V caused by an IFITM5 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thirteen had calcification of interosseous membranes, 14 had radial head
      dislocations, 10 had HPC, 9 had long bone bowing, 11 could ambulate
      without assistance, and 1 had mild unilateral mixed hearing loss.
    explanation: >-
      In this cohort, radial head dislocation occurred in 14 of 17 individuals
      (82%), which supports a VERY_FREQUENT classification.
- name: Dense Metaphyseal Bands
  description: >
    Radiodense metaphyseal bands adjacent to the growth plate are a
    characteristic radiographic feature in growing patients with OI type V.
  phenotype_term:
    preferred_term: Dense metaphyseal bands
    term:
      id: HP:0100959
      label: Dense metaphyseal bands
  evidence:
  - reference: PMID:10976985
    reference_title: "Type V osteogenesis imperfecta: a new form of brittle bone disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A radiodense metaphyseal band immediately adjacent to the growth plate
      was a constant feature in growing patients.
    explanation: >-
      The original clinical description identifies dense metaphyseal bands as a
      defining radiographic feature of OI type V in growing children.
  - reference: PMID:20872883
    reference_title: "Evolution of the radiographic appearance of the metaphyses over the first year of life in type V osteogenesis imperfecta: clues to pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We show the evolution of metaphyseal abnormalities from a rickets-like
      appearance to the classically described dense metaphyseal bands.
    explanation: >-
      This infant case report independently confirms dense metaphyseal bands as
      part of the OI type V radiographic phenotype.
- name: Recurrent Fractures
  description: >
    Moderate to severe bone fragility causes recurrent long-bone and vertebral
    fractures.
  phenotype_term:
    preferred_term: Recurrent fractures
    term:
      id: HP:0002757
      label: Recurrent fractures
  evidence:
  - reference: PMID:10976985
    reference_title: "Type V osteogenesis imperfecta: a new form of brittle bone disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These children had a history of moderate to severe increased fragility
      of long bones and vertebral bodies.
    explanation: >-
      The original OI type V description documented moderate to severe bone
      fragility affecting long bones and vertebral bodies.
- name: Bowing of the Long Bones
  description: >
    Long-bone bowing occurs in a substantial subset of individuals with OI
    type V.
  phenotype_term:
    preferred_term: Bowing of the long bones
    term:
      id: HP:0006487
      label: Bowing of the long bones
  frequency: FREQUENT
  evidence:
  - reference: PMID:23408678
    reference_title: "Phenotypic variability of osteogenesis imperfecta type V caused by an IFITM5 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thirteen had calcification of interosseous membranes, 14 had radial head
      dislocations, 10 had HPC, 9 had long bone bowing, 11 could ambulate
      without assistance, and 1 had mild unilateral mixed hearing loss.
    explanation: >-
      Long-bone bowing was reported in 9 of 17 individuals (53%), which falls
      in the FREQUENT range.
- name: Hypodontia
  description: >
    Missing permanent teeth are a common extra-skeletal manifestation and may
    occur with ectopic eruption or short molar roots.
  phenotype_term:
    preferred_term: Hypodontia
    term:
      id: HP:0000668
      label: Hypodontia
  frequency: FREQUENT
  evidence:
  - reference: PMID:23804581
    reference_title: "Osteogenesis imperfecta type V: clinical and radiographic manifestations in mutation confirmed patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, hypodontia in the permanent teeth, ectopic eruption, and short
      roots in molars were additionally observed in 11 patients.
    explanation: >-
      Hypodontia was reported in 11 of 16 mutation-confirmed patients (69%),
      which supports a FREQUENT classification.
- name: Ectopic Ossification
  description: >
    Heterotopic ossification of muscles and tendon insertion sites can occur
    and may lead to ankylosis or joint contractures.
  phenotype_term:
    preferred_term: Heterotopic ossification
    term:
      id: HP:0011986
      label: Ectopic ossification
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:23804581
    reference_title: "Osteogenesis imperfecta type V: clinical and radiographic manifestations in mutation confirmed patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heterotopic ossification in the muscles and tendon insertion sites were
      noted in four patients, which resulted in bony ankylosis or contracture
      of joints.
    explanation: >-
      Ectopic ossification was documented in 4 of 16 patients (25%), supporting
      an OCCASIONAL classification and showing clinical consequences on joint
      mobility.
  - reference: PMID:31099171
    reference_title: "Expanding the phenotypic spectrum of osteogenesis imperfecta type V including heterotopic ossification of muscle origins and attachments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CONCLUSION: Ossification of the origin and attachment of muscles seems to
      be part of the phenotype in patients with OI type V.
    explanation: >-
      This independent case report supports heterotopic ossification as part of
      the OI type V phenotype.
- name: Blue Sclerae
  description: >
    Blue sclerae are typically absent, helping distinguish OI type V from
    classical mild OI.
  phenotype_term:
    preferred_term: Blue sclerae
    term:
      id: HP:0000592
      label: Blue sclerae
  frequency: EXCLUDED
  evidence:
  - reference: PMID:23804581
    reference_title: "Osteogenesis imperfecta type V: clinical and radiographic manifestations in mutation confirmed patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Blue sclera and dentinogenesis imperfecta were not evident in any patient.
    explanation: >-
      In this mutation-confirmed cohort, blue sclerae were absent in all 16
      patients.
- name: Dentinogenesis Imperfecta
  description: >
    Dentinogenesis imperfecta is typically absent in OI type V, despite other
    dental abnormalities such as hypodontia.
  phenotype_term:
    preferred_term: Dentinogenesis imperfecta
    term:
      id: HP:0000703
      label: Dentinogenesis imperfecta
  frequency: EXCLUDED
  evidence:
  - reference: PMID:30593885
    reference_title: "Oro-dental and cranio-facial characteristics of osteogenesis imperfecta type V."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      None of the individuals had dentinogenesis imperfecta.
    explanation: >-
      This dedicated dental cohort confirms that dentinogenesis imperfecta is
      absent in OI type V.
diagnosis:
- name: Radiographic and Molecular Diagnosis
  description: >-
    Osteogenesis imperfecta type V is diagnosed from its distinctive
    radiographic hallmarks (calcification of the forearm interosseous membrane,
    radial head dislocation, a dense metaphyseal band, and hyperplastic callus)
    and confirmed by detection of the recurrent IFITM5 5'-UTR variant on
    molecular genetic testing. Unlike types I-IV, OI type V is not
    COL1A1/COL1A2-related. Hyperplastic callus should be evaluated in the OI
    type V context because it can mimic osteosarcoma; diagnostic decisions
    should integrate fracture history, imaging, IFITM5 testing, and longitudinal
    behavior before aggressive oncologic procedures.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  evidence:
  - reference: PMID:22863190
    reference_title: "A single recurrent mutation in the 5'-UTR of IFITM5 causes osteogenesis imperfecta type V."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "OI type V is an autosomal-dominant disease characterized by calcification of the forearm interosseous membrane, radial head dislocation, a subphyseal metaphyseal radiodense line, and hyperplastic callus formation"
    explanation: >-
      Defines the radiographic diagnostic hallmarks distinguishing OI type V
      from collagen-related OI, and identifies the IFITM5 5'-UTR variant as the
      molecular diagnostic target.
  - reference: DOI:10.3389/fendo.2021.622674
    reference_title: 'Case Report: Hyperplastic Callus of the Femur Mimicking Osteosarcoma in Osteogenesis Imperfecta Type V'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Misdiagnosis is a possibility due to its rarity and because patients involved are mostly in adolescence, a predisposing age for osteosarcoma.
    explanation: >-
      This case report supports adding an explicit diagnostic caution that OI
      type V hyperplastic callus can be mistaken for osteosarcoma.
- name: General OI Bone-Health Surveillance
  description: >-
    General OI bone-health surveillance applies, while management must account
    for type-V-specific risks such as hyperplastic callus that can mimic
    malignancy or be aggravated by surgery.
  evidence:
  - reference: PMID:20301472
    reference_title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DXA scans beginning at age five years with follow-up scan based on severity of OI, initial results, and pharmacologic treatment status."
    explanation: >-
      GeneReviews bone-density surveillance is part of general OI care
      applicable across OI types, including type V.
treatments:
- name: Bisphosphonate Therapy
  description: >
    Bisphosphonates may reduce fracture frequency, though hyperplastic
    callus can still occur.
  treatment_term:
    preferred_term: Bisphosphonate therapy
    term:
      id: MAXO:0000954
      label: bisphosphonate agent therapy
  evidence:
  - reference: PMID:32797291
    reference_title: "Osteogenesis imperfecta-pathophysiology and therapeutic options."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Management of patients with OI involves medical treatment by
      bisphosphonates as the most promising therapy to inhibit bone resorption
      and thereby facilitate bone formation.
    explanation: >-
      Review of OI therapeutic options identifies bisphosphonates as the primary
      medical treatment to reduce bone resorption and promote bone formation.
- name: Surgical Management
  description: >
    Orthopedic surgery for fractures and deformities should be planned
    cautiously in patients with exuberant hyperplastic callus; distinguish OI
    type V callus from osteosarcoma before aggressive oncologic procedures.
  treatment_term:
    preferred_term: Orthopedic surgery
    term:
      id: MAXO:0000004
      label: surgical procedure
  evidence:
  - reference: PMID:32797291
    reference_title: "Osteogenesis imperfecta-pathophysiology and therapeutic options."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Surgical treatment ensures pain reduction and healing without an increase
      of deformities.
    explanation: >-
      Review identifies surgical treatment as an important component of OI
      management for pain reduction and healing.
  - reference: DOI:10.3389/fendo.2021.622674
    reference_title: 'Case Report: Hyperplastic Callus of the Femur Mimicking Osteosarcoma in Osteogenesis Imperfecta Type V'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although the patient was at a predisposing age for osteosarcoma, diagnosis and treatment should be based on the medical history of the patient, imaging,and genetic testing, and sometimes even time-consuming retrospective observation.
    explanation: >-
      Supports caution before amputation or other aggressive oncologic
      procedures when an OI type V hyperplastic callus mimics osteosarcoma.
- name: Interosseous Membrane Excision
  description: >
    Surgical removal of calcified interosseous membrane to restore
    forearm rotation in selected cases.
  treatment_term:
    preferred_term: Surgical excision
    term:
      id: MAXO:0000004
      label: surgical procedure
datasets:
references:
- reference: PMID:20301472
  title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
  tags:
  - GeneReviews
  findings: []
- reference: DOI:10.1007/s00223-024-01266-5
  title: Update on the Genetics of Osteogenesis Imperfecta
  findings: []
- reference: DOI:10.1172/jci170369
  title: The IFITM5 mutation in osteogenesis imperfecta type V is associated with an ERK/SOX9-dependent osteoprogenitor differentiation defect
  findings: []
- reference: PMID:38885336
  title: The IFITM5 mutation in osteogenesis imperfecta type V is associated with an ERK/SOX9-dependent osteoprogenitor differentiation defect.
  findings: []
- reference: DOI:10.1186/s40348-020-00101-9
  title: Osteogenesis imperfecta—pathophysiology and therapeutic options
  findings: []
- reference: DOI:10.1210/endrev/bnab017
  title: 'Osteogenesis Imperfecta: Mechanisms and Signaling Pathways Connecting Classical and Rare OI Types'
  findings: []
- reference: DOI:10.3389/fendo.2021.622674
  title: 'Case Report: Hyperplastic Callus of the Femur Mimicking Osteosarcoma in Osteogenesis Imperfecta Type V'
  findings: []
📚

References & Deep Research

References

7
PMID:20301472
COL1A1- and COL1A2-Related Osteogenesis Imperfecta.
No top-level findings curated for this source.
DOI:10.1007/s00223-024-01266-5
Update on the Genetics of Osteogenesis Imperfecta
No top-level findings curated for this source.
DOI:10.1172/jci170369
The IFITM5 mutation in osteogenesis imperfecta type V is associated with an ERK/SOX9-dependent osteoprogenitor differentiation defect
No top-level findings curated for this source.
PMID:38885336
The IFITM5 mutation in osteogenesis imperfecta type V is associated with an ERK/SOX9-dependent osteoprogenitor differentiation defect.
No top-level findings curated for this source.
DOI:10.1186/s40348-020-00101-9
Osteogenesis imperfecta—pathophysiology and therapeutic options
No top-level findings curated for this source.
DOI:10.1210/endrev/bnab017
Osteogenesis Imperfecta: Mechanisms and Signaling Pathways Connecting Classical and Rare OI Types
No top-level findings curated for this source.
DOI:10.3389/fendo.2021.622674
Case Report: Hyperplastic Callus of the Femur Mimicking Osteosarcoma in Osteogenesis Imperfecta Type V
No top-level findings curated for this source.

Deep Research

2
Disorder ▸

Disorder

  • Name: Osteogenesis Imperfecta Type V
  • Category: Mendelian
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 8

Key Pathophysiology Nodes

  • IFITM5 Gain-of-Function
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1007/s00223-024-01266-5
  • DOI:10.1172/jci170369
  • DOI:10.1186/s40348-020-00101-9
  • DOI:10.1210/endrev/bnab017
  • DOI:10.3389/fendo.2021.622674
Falcon ▸
Pathophysiology description
Edison Scientific Literature 15 citations 2026-02-04T19:39:10.512306

Pathophysiology description Osteogenesis imperfecta type V is an autosomal dominant brittle bone disorder caused in nearly all cases by a recurrent IFITM5 5′-UTR variant (c.-14C>T) that creates an upstream start codon, appending five amino acids (MALEP) to the N-terminus of BRIL (MALEP‑BRIL), with evidence for a gain‑of‑function mechanism (URL: https://doi.org/10.1007/s00223-024-01266-5; Aug 2024) (jovanovic2024updateonthe pages 7-8). Authoritative review notes that elongated BRIL “does not display changes in topology, palmitoylation, or membrane localization,” supporting neomorphic activity rather than loss of function (URL: https://doi.org/10.1210/endrev/bnab017; May 2022) (jovanovic2022osteogenesisimperfectamechanisms pages 13-14). Clinically unique features include hyperplastic/hypertrophic callus, calcification of the interosseous membrane, and radial head dislocation; histology shows lamellar disorganization and paradoxical hypermineralization despite low trabecular bone mass (URL: https://doi.org/10.1210/endrev/bnab017; May 2022) (jovanovic2022osteogenesisimperfectamechanisms pages 13-14).

Recent mechanistic advances demonstrate that mutant IFITM5 perturbs early skeletal lineage decisions. A 2024 in vivo study using conditional Rosa26-knockin mice showed that expression of mutant Ifitm5 in osteo‑chondroprogenitors or chondrogenic cells, but not in mature osteoblasts, drives low bone mass, growth retardation, impaired endochondral ossification, and cartilage overgrowth with “activation of ERK signaling and downstream SOX9 protein,” and partial rescue upon ERK/SOX9 inhibition (URL: https://doi.org/10.1172/jci170369; Jun 2024) (marom2024theifitm5mutation pages 1-2). Together, these data support a model in which MALEP‑BRIL dysregulates ERK→SOX9 signaling in periosteal and growth plate progenitors, arresting osteogenic differentiation and contributing to OI‑V‑specific ossification phenotypes.

Core pathophysiology - Primary mechanisms: - Neomorphic, cell‑context–specific activity of MALEP‑BRIL alters early skeletal cell fate, impairing osteo‑chondroprogenitor progression toward osteoblasts and favoring chondrogenic states via ERK/SOX9 signaling; inhibition of ERK/SOX9 partially rescues skeletal defects in vivo (URL: https://doi.org/10.1172/jci170369; Jun 2024) (marom2024theifitm5mutation pages 1-2). - Osteoblast mineralization biology is altered: BRIL expression rises with osteoblast maturation/mineralization; OI‑V osteoblasts can show increased in vitro mineralization, and bone is highly mineralized by qBEI despite decreased bone volume and bone formation rate in biopsies (URL: https://doi.org/10.1007/s00223-024-01266-5; Aug 2024; URL: https://doi.org/10.1210/endrev/bnab017; May 2022) (jovanovic2024updateonthe pages 7-8, jovanovic2022osteogenesisimperfectamechanisms pages 13-14). - Periosteal progenitor pool expansion and dysregulated extraosseous ossification provide a cellular basis for hyperplastic callus and interosseous membrane calcification (URL: https://doi.org/10.1172/jci170369; Jun 2024; URL: https://doi.org/10.1210/endrev/bnab017; May 2022) (marom2024theifitm5mutation pages 1-2, jovanovic2022osteogenesisimperfectamechanisms pages 13-14). - Dysregulated pathways: - ERK/MAPK → SOX9 axis: mutant IFITM5 increases ERK activation and SOX9 abundance, shifting osteo‑chondroprogenitors toward chondrogenesis; pathway inhibition partially rescues phenotype (URL: https://doi.org/10.1172/jci170369; Jun 2024) (marom2024theifitm5mutation pages 1-2). - Osteoblast cytokine/PI3K–AKT/calcineurin–NFAT programs and inflammatory mediators (e.g., PTGS2/COX‑2, PGE2) are induced downstream of MALEP‑BRIL in vitro, with sensitivity to FK506/cyclosporins and PI3K inhibition (LY294002), suggesting BRIL‑dependent modulation of membrane‑proximal signaling (2024 research synthesis) (tiranardi2024investigationoftherapeutics pages 83-86, tiranardi2024investigationoftherapeutics pages 17-21). - Potential linkage to PEDF (SERPINF1) pathways in mineralization biology has been noted, suggesting convergence across OI types (URL: https://doi.org/10.1186/s40348-020-00101-9; Aug 2020; URL: https://doi.org/10.1007/s00223-024-01266-5; Aug 2024) (etich2020osteogenesisimperfecta—pathophysiologyand pages 7-8, jovanovic2024updateonthe pages 7-8). - Cellular processes affected: - Early lineage specification and endochondral ossification: impaired chondrocyte‑to‑osteoblast progression, abnormal growth plate architecture, ectopic chondrogenesis, and expansion of periosteal skeletal progenitors (URL: https://doi.org/10.1172/jci170369; Jun 2024) (marom2024theifitm5mutation pages 1-2). - Osteoblast differentiation/mineralization: cell‑autonomous arrest and hypomineralization in certain models; in humanized mouse contexts, context‑dependent increases in osteoblast markers (ALPL) highlight species and developmental timing effects (2023 model characterization) (robinson2023characterizationofhumanized pages 72-77). - Bone remodeling: decreased bone formation rate with increased osteocyte number/size and high tissue mineralization suggests impaired lamellar organization and remodeling dynamics (URL: https://doi.org/10.1210/endrev/bnab017; May 2022) (jovanovic2022osteogenesisimperfectamechanisms pages 13-14).

Key molecular players - Genes/Proteins (HGNC): - IFITM5 (HGNC:19110), encoding BRIL; pathogenic variant c.-14C>T (MALEP‑BRIL) is causal in OI‑V and shows gain‑of‑function properties (URL: https://doi.org/10.1007/s00223-024-01266-5; Aug 2024; URL: https://doi.org/10.1210/endrev/bnab017; May 2022) (jovanovic2024updateonthe pages 7-8, jovanovic2022osteogenesisimperfectamechanisms pages 13-14). - SOX9 (HGNC:11195) and ERK/MAPK components (e.g., MAPK1/MAPK3) are implicated as downstream effectors whose activation is sufficient to drive progenitor defects; inhibition partially rescues skeletal phenotypes (URL: https://doi.org/10.1172/jci170369; Jun 2024) (marom2024theifitm5mutation pages 1-2). - Potential interactors/modulators: FKBP11 and CAML; MEF2/NFATc transcriptional programs; COX‑2 (PTGS2) and PI3K–AKT signaling implicated from transcriptomic/perturbational data (2024 synthesis) (tiranardi2024investigationoftherapeutics pages 83-86, tiranardi2024investigationoftherapeutics pages 17-21). - Comparative pathways: PEDF (SERPINF1) discussed in relation to mineralization and osteoclast coupling (URL: https://doi.org/10.1186/s40348-020-00101-9; Aug 2020; URL: https://doi.org/10.1007/s00223-024-01266-5; Aug 2024) (etich2020osteogenesisimperfecta—pathophysiologyand pages 7-8, jovanovic2024updateonthe pages 7-8). - Chemical entities (CHEBI; where applicable): - Research probes: tacrolimus/FK506 (calcineurin inhibitor), cyclosporins, LY294002 (PI3K inhibitor), PGE2 (COX‑2 product); pathway modulation informs BRIL‑dependent signaling (2024 synthesis) (tiranardi2024investigationoftherapeutics pages 83-86, tiranardi2024investigationoftherapeutics pages 17-21). - Therapeutics used in OI care: bisphosphonates (anti‑resorptives); mechanism-based denosumab highlighted for SERPINF1‑related OI with implications for mineralization pathways (URL: https://doi.org/10.1186/s40348-020-00101-9; Aug 2020) (etich2020osteogenesisimperfecta—pathophysiologyand pages 7-8). - Cell types (CL): - Osteo‑chondroprogenitors (skeletal progenitors in periosteum/growth plate) show primary defects under mutant IFITM5 (URL: https://doi.org/10.1172/jci170369; Jun 2024) (marom2024theifitm5mutation pages 1-2). - Chondrocytes and osteoblasts, with reduced chondrocyte‑to‑osteoblast transition and context‑dependent osteoblast dysfunction (marom2024theifitm5mutation pages 1-2, robinson2023characterizationofhumanized pages 72-77). - Osteocytes increased in number and size in patient bone histology (jovanovic2022osteogenesisimperfectamechanisms pages 13-14). - Anatomical locations (UBERON): - Periosteum and diaphyseal cortical regions (progenitor niches affected); growth plate cartilage (endochondral ossification); interosseous membrane of forearm (pathologic calcification); sites of hyperplastic callus (marom2024theifitm5mutation pages 1-2, jovanovic2022osteogenesisimperfectamechanisms pages 13-14).

Biological processes for GO annotation (disrupted) - Osteoblast differentiation and mineralization; ossification and endochondral bone formation; regulation of ERK1/2 cascade; chondrocyte differentiation and cartilage development; extracellular matrix organization and mineralization; inflammatory response and cytokine‑mediated signaling (marom2024theifitm5mutation pages 1-2, jovanovic2024updateonthe pages 7-8, jovanovic2022osteogenesisimperfectamechanisms pages 13-14, tiranardi2024investigationoftherapeutics pages 83-86, tiranardi2024investigationoftherapeutics pages 17-21).

Cellular components - Plasma membrane microdomains where BRIL localizes and assembles cytokine/kinase signaling complexes; periosteal and growth plate microenvironments for progenitor activity; extracellular matrix and mineralization front; osteocyte lacuno‑canalicular network reflecting remodeling abnormalities (jovanovic2022osteogenesisimperfectamechanisms pages 13-14, tiranardi2024investigationoftherapeutics pages 83-86, marom2024theifitm5mutation pages 1-2).

Disease progression - Initial trigger: germline IFITM5 c.-14C>T yields MALEP‑BRIL expressed in bone‑restricted lineage cells (jovanovic2024updateonthe pages 7-8, jovanovic2022osteogenesisimperfectamechanisms pages 13-14). - Early developmental stage: ERK→SOX9 activation in osteo‑chondroprogenitors impairs endochondral ossification, expands periosteal progenitors, and reduces chondrocyte‑to‑osteoblast transition (marom2024theifitm5mutation pages 1-2). - Bone formation/remodeling: decreased bone formation rate with hypermineralized, lamellarly disorganized matrix and increased osteocyte density/size (jovanovic2022osteogenesisimperfectamechanisms pages 13-14). - Clinical manifestations: recurrent fractures with excessive callus response (hyperplastic callus) and progressive ossification of interosseous membrane; variable scoliosis and limb deformities (jovanovic2022osteogenesisimperfectamechanisms pages 13-14).

Phenotypic manifestations (HPO examples) - Abnormal bone mineral density and hypermineralized bone matrix; decreased trabecular bone volume; hyperplastic callus; calcification of interosseous membrane; radial head dislocation; scoliosis; impaired growth and bone deformities (jovanovic2022osteogenesisimperfectamechanisms pages 13-14, jovanovic2024updateonthe pages 7-8). - Quantitative examples: review notes decreased bone volume fraction with high mineralization and reduced bone formation rate in iliac crest biopsies; “about two‑thirds” of OI‑V show hyperplastic callus or scoliosis (URL: https://doi.org/10.1210/endrev/bnab017; May 2022) (jovanovic2022osteogenesisimperfectamechanisms pages 13-14). - Mouse–human links: mutant Ifitm5 expression in progenitors recapitulates impaired endochondral ossification and cartilage overgrowth; pathway rescue validates causality (URL: https://doi.org/10.1172/jci170369; Jun 2024) (marom2024theifitm5mutation pages 1-2).

Unique biology of hyperplastic callus and interosseous membrane calcification - Hyperplastic callus likely reflects dysregulated periosteal progenitor expansion and extraosseous ossification under aberrant ERK/SOX9 signaling, consistent with progenitor‑biased pathophysiology (marom2024theifitm5mutation pages 1-2, jovanovic2022osteogenesisimperfectamechanisms pages 13-14). Case literature emphasizes the sarcoma mimicry risk during massive callus formation and the value of genetic testing (URL: https://doi.org/10.3389/fendo.2021.622674; Apr 2021) (etich2020osteogenesisimperfecta—pathophysiologyand pages 7-8). - Interosseous membrane calcification aligns with OI‑V’s propensity for ectopic ossification in fibrous tissues adjacent to bone, consistent with altered osteo‑chondrogenic signaling (jovanovic2022osteogenesisimperfectamechanisms pages 13-14).

Recent developments and expert analyses (2023–2024 emphasis) - 2024 mechanistic advance: Identification of an “ERK/SOX9‑dependent osteoprogenitor differentiation defect” and partial rescue by pathway inhibition (direct quote: mutant IFITM5 disrupted skeletal homeostasis “in part by activating ERK signaling and downstream SOX9 protein, and inhibition of these pathways partially rescued the phenotype”) (URL: https://doi.org/10.1172/jci170369; Jun 2024) (marom2024theifitm5mutation pages 1-2). - 2024 genetics update: Consolidates IFITM5 c.-14C>T as the dominant OI‑V driver; emphasizes altered mineralization biology and links to other OI mechanisms (URL: https://doi.org/10.1007/s00223-024-01266-5; Aug 2024) (jovanovic2024updateonthe pages 7-8). - Context from humanized models (2023): demonstrates cell‑autonomous osteoblastogenesis arrest and timing/species‑dependent phenotypes, including increased serum ALPL with post‑natal human BRIL expression (modeling limitations acknowledged) (2023) (robinson2023characterizationofhumanized pages 72-77). - Consensus/expert review: OI‑V shows hyperplastic callus and interosseous ossification; bone histology with decreased BFR, high mineralization, and increased osteocytes supports a distinct pathophysiology relative to collagen‑defective OI (URL: https://doi.org/10.1210/endrev/bnab017; May 2022) (jovanovic2022osteogenesisimperfectamechanisms pages 13-14).

Current applications and real‑world implementations - Standard-of-care across OI includes bisphosphonates to decrease resorption and facilitate formation; mechanism‑based antiresorptives (e.g., denosumab) are used in specific genetic contexts (SERPINF1) and highlight mineralization/coupling pathways relevant to OI‑V biology (URL: https://doi.org/10.1186/s40348-020-00101-9; Aug 2020) (etich2020osteogenesisimperfecta—pathophysiologyand pages 7-8). - Diagnostic implications: Because hyperplastic callus can mimic osteosarcoma, longitudinal imaging and genetic testing for IFITM5 are critical for accurate diagnosis and limb‑sparing management (URL: https://doi.org/10.3389/fendo.2021.622674; Apr 2021) (etich2020osteogenesisimperfecta—pathophysiologyand pages 7-8). - Translational direction: The ERK/SOX9 pathway represents an actionable target; preclinical rescue with pathway inhibition supports exploration of targeted therapies for OI‑V (URL: https://doi.org/10.1172/jci170369; Jun 2024) (marom2024theifitm5mutation pages 1-2).

Gene/protein annotations with ontology terms (selected) - IFITM5 (HGNC:19110): bone‑restricted membrane protein BRIL; neomorphic MALEP‑BRIL causes OI‑V; processes: osteoblast differentiation, bone mineralization; components: plasma membrane; pathways: ERK/MAPK, PI3K–AKT, calcineurin–NFAT; evidence (jovanovic2024updateonthe pages 7-8, jovanovic2022osteogenesisimperfectamechanisms pages 13-14, marom2024theifitm5mutation pages 1-2, tiranardi2024investigationoftherapeutics pages 83-86, tiranardi2024investigationoftherapeutics pages 17-21). - SOX9 (HGNC:11195): chondrogenesis transcription factor; increased activity drives progenitor bias, rescue by pathway inhibition; processes: chondrocyte differentiation, endochondral ossification; evidence (marom2024theifitm5mutation pages 1-2). - MAPK/ERK (e.g., MAPK1/3): signaling cascade activated by mutant IFITM5 in progenitors; processes: ERK1/2 cascade, cell fate determination; evidence (marom2024theifitm5mutation pages 1-2). - PTGS2 (COX‑2): inflammatory mediator induced by MALEP‑BRIL in vitro; processes: prostaglandin biosynthesis, inflammatory response; evidence (tiranardi2024investigationoftherapeutics pages 83-86, tiranardi2024investigationoftherapeutics pages 17-21).

Phenotype associations (HPO; selected) - Hyperplastic callus (massive hypertrophic callus) (jovanovic2022osteogenesisimperfectamechanisms pages 13-14, etich2020osteogenesisimperfecta—pathophysiologyand pages 7-8) - Calcification/ossification of interosseous membrane (jovanovic2022osteogenesisimperfectamechanisms pages 13-14) - Radial head dislocation (jovanovic2022osteogenesisimperfectamechanisms pages 13-14) - Low bone mass with hypermineralized bone and decreased BFR; increased osteocyte number/size (jovanovic2022osteogenesisimperfectamechanisms pages 13-14) - Scoliosis (co‑occurring feature in a substantial subset) (jovanovic2022osteogenesisimperfectamechanisms pages 13-14)

Cell type involvement (CL; selected) - Osteo‑chondroprogenitor (skeletal progenitor) – primary defect locus (marom2024theifitm5mutation pages 1-2) - Chondrocyte – ectopic/expanded with impaired transition (marom2024theifitm5mutation pages 1-2) - Osteoblast – differentiation/mineralization altered; context‑dependent effects (robinson2023characterizationofhumanized pages 72-77, jovanovic2024updateonthe pages 7-8) - Osteocyte – increased number/size (jovanovic2022osteogenesisimperfectamechanisms pages 13-14)

Anatomical locations (UBERON; selected) - Periosteum and diaphyseal cortex (progenitor pool, extraosseous ossification) (marom2024theifitm5mutation pages 1-2) - Growth plate cartilage (endochondral ossification defect) (marom2024theifitm5mutation pages 1-2) - Interosseous membrane of forearm (ectopic calcification) (jovanovic2022osteogenesisimperfectamechanisms pages 13-14)

Chemical entities (CHEBI; selected research/therapeutic) - Bisphosphonates (antiresorptives) – clinical standard in OI (etich2020osteogenesisimperfecta—pathophysiologyand pages 7-8) - Denosumab – mechanism‑based therapy in SERPINF1‑related OI, mechanistic relevance to mineralization/coupling (etich2020osteogenesisimperfecta—pathophysiologyand pages 7-8) - LY294002 (PI3K inhibitor), tacrolimus/FK506, cyclosporins – in vitro probes modulating MALEP‑BRIL downstream programs (tiranardi2024investigationoftherapeutics pages 83-86, tiranardi2024investigationoftherapeutics pages 17-21)

Evidence items with PMIDs/links and publication dates - Marom et al., The IFITM5 mutation in osteogenesis imperfecta type V is associated with an ERK/SOX9‑dependent osteoprogenitor differentiation defect. Journal of Clinical Investigation. URL: https://doi.org/10.1172/jci170369; Publication: Jun 2024 (marom2024theifitm5mutation pages 1-2). - Jovanovic, Marini. Update on the Genetics of Osteogenesis Imperfecta. Calcified Tissue International. URL: https://doi.org/10.1007/s00223-024-01266-5; Publication: Aug 2024 (jovanovic2024updateonthe pages 7-8). - Jovanovic, Guterman‑Ram, Marini. Osteogenesis Imperfecta: Mechanisms and signaling pathways connecting classical and rare OI types. Endocrine Reviews. URL: https://doi.org/10.1210/endrev/bnab017; Publication: May 2022 (jovanovic2022osteogenesisimperfectamechanisms pages 13-14, jovanovic2022osteogenesisimperfectamechanisms pages 11-12). - Robinson S. Characterization of Humanized Mouse Models for Type V and Atypical Type VI Osteogenesis Imperfecta. 2023 (model report; URL not captured in this extract) (robinson2023characterizationofhumanized pages 72-77). - Etich et al. Osteogenesis imperfecta—pathophysiology and therapeutic options. Molecular and Cellular Pediatrics. URL: https://doi.org/10.1186/s40348-020-00101-9; Publication: Aug 2020 (etich2020osteogenesisimperfecta—pathophysiologyand pages 7-8). - Tiranardi M. Investigation of therapeutics for treating osteogenesis imperfecta type V. 2024 (preprint/unknown journal; mechanistic synthesis including PI3K/AKT, NFATc, PTGS2) (tiranardi2024investigationoftherapeutics pages 17-21, tiranardi2024investigationoftherapeutics pages 83-86). - Deng et al. Case Report: Hyperplastic Callus of the Femur Mimicking Osteosarcoma in OI‑V. Frontiers in Endocrinology. URL: https://doi.org/10.3389/fendo.2021.622674; Publication: Apr 2021 (etich2020osteogenesisimperfecta—pathophysiologyand pages 7-8).

Direct quotes (key statements) - “Mutant IFITM5 disrupted early skeletal homeostasis in part by activating ERK signaling and downstream SOX9 protein, and inhibition of these pathways partially rescued the phenotype in mutant animals.” (Marom et al., JCI 2024) (marom2024theifitm5mutation pages 1-2). - MALEP‑BRIL “does not display changes in topology, palmitoylation, or membrane localization,” consistent with a gain‑of‑function mechanism (Jovanovic et al., Endocrine Reviews 2022) (jovanovic2022osteogenesisimperfectamechanisms pages 13-14). - OI‑V hallmarks include “hyperplastic callus formation after fractures and excessive ossification of the membrana interossea” (Etich et al., 2020) (etich2020osteogenesisimperfecta—pathophysiologyand pages 7-8).

Expert opinions and analysis - Genetics/nosology: Contemporary nosology and genetics reviews consolidate IFITM5‑driven OI‑V as a distinct, non‑collagen OI with unique ossification biology and suggest mechanistic convergence among OI types via mineralization pathways (Jovanovic & Marini 2024; Jovanovic et al. 2022) (jovanovic2024updateonthe pages 7-8, jovanovic2022osteogenesisimperfectamechanisms pages 13-14). - Management implications: Anti‑resorptive therapy remains a mainstay across OI; mechanistic targeting of signaling (e.g., ERK/SOX9) is a leading translational avenue for OI‑V based on 2024 preclinical rescue (etich2020osteogenesisimperfecta—pathophysiologyand pages 7-8, marom2024theifitm5mutation pages 1-2).

Gaps and future directions - Precise BRIL interactome and ligand context at the osteoblast membrane remain incompletely resolved; transcriptomic data implicate PI3K–AKT and calcineurin–NFAT downstream of MALEP‑BRIL and suggest cytokine co‑receptor functions (2024 synthesis) (tiranardi2024investigationoftherapeutics pages 83-86, tiranardi2024investigationoftherapeutics pages 17-21). - Humanized mouse models underscore developmental timing and species sequence constraints; further models that recapitulate OI‑V post‑natal phenotypes are needed (robinson2023characterizationofhumanized pages 72-77).

Summary OI‑V is a BRIL‑driven, non‑collagen OI characterized by neomorphic signaling that redirects osteo‑chondroprogenitor fate through ERK/SOX9, yielding impaired endochondral ossification, periosteal progenitor expansion, and distinct ossification phenotypes including hyperplastic callus and interosseous membrane calcification. Bone shows decreased formation with paradoxically high mineralization and increased osteocyte density/size. Recent 2024 in vivo work provides causal and partially rescuable pathway evidence, laying the groundwork for targeted therapeutics alongside current anti‑resorptive management (marom2024theifitm5mutation pages 1-2, jovanovic2024updateonthe pages 7-8, jovanovic2022osteogenesisimperfectamechanisms pages 13-14, etich2020osteogenesisimperfecta—pathophysiologyand pages 7-8, tiranardi2024investigationoftherapeutics pages 83-86, tiranardi2024investigationoftherapeutics pages 17-21, robinson2023characterizationofhumanized pages 72-77).

References

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  2. (jovanovic2022osteogenesisimperfectamechanisms pages 13-14): Milena Jovanovic, Gali Guterman-Ram, and Joan C Marini. Osteogenesis imperfecta: mechanisms and signaling pathways connecting classical and rare oi types. Endocrine reviews, 43:61-90, May 2022. URL: https://doi.org/10.1210/endrev/bnab017, doi:10.1210/endrev/bnab017. This article has 182 citations and is from a domain leading peer-reviewed journal.

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