Osteogenesis Imperfecta Type VI

1. Disease Information

Overview

Osteogenesis Imperfecta Type VI (OI6) is an extremely rare, severe autosomal recessive skeletal dysplasia characterized by bone fragility and a distinctive mineralization defect, caused by loss-of-function mutations in the SERPINF1 gene encoding pigment epithelium-derived factor (PEDF). It was first delineated by Glorieux et al. in 2002 as a group of patients initially classified as OI type IV who share a unique set of clinical, histological, and biochemical features not explained by collagen structural defects (PMID: 11771665). Unlike the classical dominant OI types (I–IV), OI type VI is distinguished by normal type I collagen, an absence of dentinogenesis imperfecta and hearing loss, and the pathognomonic "fish-scale" lamellar pattern observed by polarized-light bone histomorphometry. Fewer than 50 cases have been reported in the world literature.

Key Identifiers

Synonyms and Alternative Names

• OI Type VI
• Osteogenesis imperfecta with mineralization defect
• OI6
• Brittle bone disease type VI
• Pigment epithelium-derived factor (PEDF) deficiency

2. Etiology

Primary Disease Cause

OI type VI is caused exclusively by biallelic loss-of-function variants in SERPINF1 (chromosome 17p13.3), which encodes the secreted glycoprotein pigment epithelium-derived factor (PEDF). All disease-causing alleles reported to date result in complete or near-complete abolition of PEDF secretion. Unlike OI types I–IV, the type I collagen genes (COL1A1, COL1A2) are structurally normal. PEDF's roles in bone homeostasis—inhibiting osteoclastogenesis, promoting osteoblast differentiation, and regulating mineralization—are thus disrupted (PMID: 21826736; PMID: 24523041).

Genetic Risk Factors

• Autosomal recessive inheritance: Both parents are obligate heterozygous carriers. The recurrence risk for sibling offspring of carrier couples is 25% per pregnancy.
• Consanguinity: OI type VI is enriched in consanguineous populations. In a large Indian cohort, SERPINF1 variants accounted for approximately 12.5% of the autosomal recessive OI population, attributable to higher background rates of consanguinity (PMC10323215).
• Founder mutations: A 5-bp duplication in exon 3 of SERPINF1, c.261_265dup (p.Leu89Argfs26), exhibits a strong founder effect in the Tuvan population* of Southern Siberia, with an estimated carrier frequency of 1:114 and disease prevalence of approximately 1:52,375 in that isolate (PMC12250282).
• No known genetic modifier genes significantly altering OI6 penetrance or expressivity have been identified. Penetrance is complete for biallelic null alleles.

Environmental Risk Factors

No environmental factors have been shown to cause or substantially modify OI type VI risk, which is monogenic. However: - Calcium and vitamin D insufficiency can worsen the already-poor bone mineralization phenotype and exacerbate fracture burden. - Physical trauma from standing and ambulation precipitates the first fractures (onset 4–18 months).

3. Phenotypes

Clinical Phenotype Summary

OI type VI presents with a characteristically moderate-to-severe and progressive skeletal phenotype. The defining clinical features that distinguish it from other OI types include the absence of fractures at birth, absence of dentinogenesis imperfecta, normal or faintly blue (not deep blue) sclerae, and absent sensorineural hearing loss (PMID: 11771665; PMC12250282).

Biochemical phenotypes: - Elevated serum alkaline phosphatase (ALP): ALPL levels in children with OI6 are elevated compared with age-matched OI type IV patients (409 ± 145 U/L vs. 295 ± 95 U/L; PMID: 11771665). HP:0003155 (Elevated alkaline phosphatase) - Undetectable serum PEDF: Circulating PEDF (~100 nM in normal individuals) is completely absent or dramatically reduced in OI6 patients (PMID: 21826736). This is pathognomonic.

Histopathology phenotype: - Fish-scale lamellar pattern (polarized light): Bone biopsy reveals an irregular "fish-scale" arrangement of bone lamellae visible under polarized light microscopy — the histological hallmark of OI6, not seen in other OI types (PMID: 11771665; PMID: 25554599). - Increased osteoid volume: Excessive unmineralized osteoid accumulates, reflecting a prolonged mineral lag time and impaired matrix mineralization. - Increased osteocyte number - Coexistence of hypermineralized zones and hypomineralized osteoid seams at nano-scale (PMID: 25554599): unusual heterogeneous mineral particle population.

Quality of Life Impact

OI type VI severely impairs quality of life. All patients in published series lose independent ambulation; 2 of 4 patients in the Tuvan cohort never achieved unsupported sitting (PMC12250282). Progressive spinal deformities cause pain, respiratory compromise, and loss of balance. BAMF and GMFM mobility scores are low and tend to stabilize or marginally improve only with aggressive anti-resorptive therapy (PMC4180531).

4. Genetic and Molecular Information

Causal Gene: SERPINF1 (HGNC:8824)

SERPINF1 encodes the 418-amino-acid secreted glycoprotein PEDF (pigment epithelium-derived factor), a member of the non-inhibitory serpin superfamily. The protein contains a collagen-binding domain (N-terminal region), an antiangiogenic domain, and a neurotrophic domain. PEDF is ubiquitously expressed but particularly abundant in bone (osteoblasts, osteocytes), eye (retinal pigment epithelium), and liver (PMID: 21826736).

• Gene locus: 17p13.3
• RefSeq mRNA: NM_002615.6
• UniProt: P36955

Pathogenic Variant Types

All OI6-causing variants result in loss of function (PEDF absent from serum). Variant types include:

• Variant classification: All definitively pathogenic variants are autosomal recessive. De novo variants are not described; both parents are obligate carriers.
• Allele frequency (gnomAD): Individual SERPINF1 LOF alleles are individually very rare (heterozygous allele frequency typically <0.001); compound heterozygosity is common outside founder populations.
• Origin: Germline; somatic OI6 not described.
• Functional consequence: Null mutations → nonsense-mediated decay or premature stop → absent PEDF protein. Missense/in-frame variants → protein misfolding → ER retention → ER stress → no secreted protein (PMID:25868797; ScienceDirect article on ER stress 2025).

Modifier Genes / Epigenetics

No well-validated modifier genes for OI6 expressivity have been identified. Notably, a rare IFITM5 S40L mutation (causing OI type V) paradoxically reduces PEDF secretion from osteoblasts, producing an "atypical OI type VI" phenotype—demonstrating that PEDF reduction is the proximate cause rather than SERPINF1 genotype per se (PMID:24523041). Epigenetic contributions are not established for OI6.

5. Environmental Information

No environmental factors are causal in OI type VI, which is an entirely monogenic condition. Environmental modifiers of clinical severity include: - Physical trauma and weight-bearing: The onset of fractures coincides with early ambulation (4–18 months), indicating that mechanical loading precipitates fractures in the setting of extreme bone fragility. - Calcium and vitamin D intake: Suboptimal calcium/vitamin D worsens the mineralization defect. All published treatment protocols include calcium (500–1000 mg/day) and vitamin D supplementation alongside pharmacotherapy (PMC4180531). - Immobilization: Prolonged immobilization after fractures accelerates bone resorption and worsens osteopenia, creating a vicious cycle.

6. Mechanism / Pathophysiology

Overview of Pathogenic Cascade

The fundamental mechanism of OI6 is absence of secreted PEDF, leading to dysregulated bone remodeling, defective matrix mineralization, and excessive osteoid accumulation. PEDF normally exerts multiple protective effects in bone:

6a. RANKL/OPG Axis: Osteoclast Overactivation

PEDF normally upregulates osteoprotegerin (OPG) expression in osteoblasts, thereby inhibiting RANKL-mediated osteoclast differentiation and activation. PEDF also directly antagonizes RANKL-mediated cell survival signals in osteoclast precursors (PMID:19945427). In the absence of PEDF, the OPG:RANKL ratio is shifted toward RANKL, promoting osteoclastogenesis and excessive bone resorption. This explains the limited efficacy of bisphosphonates (which require mineralized bone matrix for deposition) and the superior efficacy of denosumab (anti-RANKL monoclonal antibody) in OI6 (PMC4180531).

• GO process: GO:0030316 (osteoclast differentiation)
• GO process: GO:0060352 (cell adhesion molecule production involved in inflammatory response) — secondary
• CL terms: CL:0000092 (osteoclast), CL:0000062 (osteoblast)

6b. SOST/Sclerostin Dysregulation: Impaired Osteoblast Differentiation

PEDF suppresses expression of SOST (encoding sclerostin) and other osteocyte-associated genes (MEPE, DMP1) in osteocytes via ERK/GSK-3β/β-catenin signaling. ERK activation by PEDF inactivates GSK-3β, stabilizing β-catenin and permitting nuclear Wnt target gene activation to support osteoblastogenesis. Without PEDF, sclerostin is overexpressed, Wnt signaling is inhibited, and osteoblast gene expression (RUNX2, osteocalcin, BSP, COL1A1*) is reduced (PMID:30076958; PMID:30607618).

• GO process: GO:0060070 (canonical Wnt signaling pathway)
• GO process: GO:0010832 (negative regulation of myotube differentiation) — adjacent
• Cell type: CL:0000137 (osteocyte)

6c. Wnt3a Antagonism at Terminal Osteoblast Differentiation

PEDF blocks LRP6 (a Wnt co-receptor), suppressing Wnt3a signaling at the late stage of osteoblast differentiation. Continuous Wnt3a exposure at this stage paradoxically reduces mineralization by 40%. PEDF therefore acts as a context-dependent Wnt inhibitor at terminal differentiation, and its absence unleashes inappropriate Wnt3a activity that disrupts the osteoblast-to-osteocyte transition and the initiation of matrix mineralization (PMC4970601). This explains the increased osteoid (unmineralized matrix) with architecturally abnormal lamellae.

• GO process: GO:0030282 (bone mineralization)
• GO process: GO:0043062 (extracellular structure organization)

6d. PEDF-TGF-β Antagonism

PEDF functionally antagonizes TGF-β signaling. Loss of PEDF leads to activated TGF-β signaling in osteoblasts, which delays osteoblast maturation and ECM mineralization while simultaneously stimulating pro-angiogenic factors (e.g., VEGF). In the Serpinf1−/− mouse model, TGF-β stimulation and PEDF deficiency produce additive suppression of osteogenic markers (Kang et al. 2022, JBMR, PMID:35212013). This provides a rationale for combined PEDF replacement + TGF-β antibody therapeutic strategies. Increased angiogenesis may also contribute to the structural vascular pathogenesis.

• GO process: GO:0007179 (TGF-β receptor signaling pathway)
• GO process: GO:0001525 (angiogenesis)

6e. ER Stress / Autophagy (In-Frame / Missense Variants)

For patients harboring in-frame or missense SERPINF1 mutations (rather than truncating null alleles), mutant PEDF protein is synthesized but retained in the endoplasmic reticulum due to misfolding. This triggers ER stress and the unfolded protein response (UPR), activating ER-associated degradation (ERAD) and autophagy as compensatory mechanisms (ScienceDirect 2025, PMID forthcoming). The net result is osteoblast apoptosis and impaired differentiation, convergent on the same downstream phenotype. ER stress and autophagy pathways are emerging as therapeutic targets for SERPINF1 missense-variant OI6.

• GO process: GO:0034976 (response to endoplasmic reticulum stress)
• GO process: GO:0006914 (autophagy)

6f. Anti-Adipogenic / Anti-Angiogenic Functions

PEDF inhibits adipogenesis (binding adipose triglyceride lipase, suppressing PPARγ). In the Serpinf1−/− mouse, total body adiposity increases by ~50%, suggesting PEDF-null OI6 may have altered mesenchymal stem cell fate allocation (reduced osteoblast, increased adipocyte differentiation from bone marrow progenitors) (PMC8755987).

Summary Causal Chain

Biallelic SERPINF1 LOF mutations
    ↓
Absent PEDF in circulation and bone ECM
    ↓
[Branch A] ↓OPG, ↑RANKL → Osteoclast overactivation → Excessive bone resorption
[Branch B] ↑Sclerostin → ↓Wnt signaling → Impaired osteoblast differentiation
[Branch C] ↑Wnt3a at terminal differentiation → Disrupted osteoblast-osteocyte transition
[Branch D] ↑TGF-β signaling → Delayed osteoblast maturation + ↑pro-angiogenic factors
[Branch E] (Missense only) ER retention of PEDF → ER stress → Osteoblast apoptosis
    ↓ (convergence)
Defective ECM mineralization + Excess unmineralized osteoid + Structural lamellar disorganization
    ↓
Fish-scale lamellation pattern; elevated ALP; absent serum PEDF
    ↓
Bone fragility → Fractures, deformity, short stature, kyphoscoliosis

Tissue / Cell Types Involved

Anatomical Structures Affected (UBERON)

7. Anatomical Structures Affected

See detailed summary in section 6 (Mechanism). Briefly:

• Primary: Long bones (bilateral), vertebral column (multilevel compression fractures), thoracic cage (thin ribs, bell-shaped chest), bone extracellular matrix
• Secondary: Respiratory function (from thoracic restriction and kyphoscoliosis); neuromuscular function (hypotonia, motor delay)
• Subcellular: Endoplasmic reticulum (ER retention of missense PEDF), extracellular matrix (excessive osteoid accumulation)

The eye (retinal pigment epithelium, where PEDF was originally discovered) is not clinically affected in OI6 despite high PEDF expression there.

8. Temporal Development

Onset

• Perinatal/neonatal period: No fractures at birth (important distinguishing feature from OI types II/III). Skeletal appearance is normal at birth.
• Infancy (4–18 months): Fractures begin with the onset of weight-bearing and ambulation. This is the canonical age-of-onset for OI6 (PMID: 11771665; PMC12250282).
• Early childhood: Progressive long bone deformities, vertebral compression fractures; growth retardation becomes apparent.

Progression

OI6 follows a relentlessly progressive clinical course: - Fracture burden accumulates over childhood (reported range: 8–200 total fractures across published patients, PMC12250282). - Skeletal deformities worsen progressively: bowing of long bones becomes multiplanar, vertebral compression fractures lead to loss of height, kyphoscoliosis progresses and may require surgical stabilization in adolescence. - Mobility generally decreases: all affected patients in one cohort eventually lost independent ambulation; 2 of 4 never achieved unsupported sitting. - No spontaneous remission occurs; disease is lifelong and progressive without intervention.

Disease Stage Patterns

9. Inheritance and Population

Inheritance

• Autosomal recessive (AR)
• Penetrance is complete for confirmed biallelic null alleles
• Expressivity: Variable (8–200 lifetime fractures in published cases); may partly reflect variant type (null vs. missense), genetic background, and treatment access
• No genetic anticipation (not a trinucleotide repeat disorder)
• Consanguinity: A significant risk factor; many published cases involve consanguineous parents

Epidemiology

Population Demographics

• Global: Reported in patients from France, Italy, Russia (Tuva), India, Korea, China, Ecuador, Middle East, and North Africa — no single ethnic group predominates globally.
• Tuvan population (Southern Siberia): Strong founder effect (c.261_265dup); likely the highest known local prevalence due to long-term population isolation (PMC12250282).
• Indian subcontinent: Disproportionately represented among AR-OI cohorts, likely due to consanguinity rates (PMC10323215).
• Age distribution: A pediatric disease. Most reported patients are children/adolescents; adult cases documented but rare.

10. Diagnostics

Clinical Diagnostic Criteria

OI6 was originally distinguished from type IV OI by the combination of (PMID: 11771665): 1. Fractures first documented between 4 and 18 months 2. Absence of fractures at birth 3. White or faintly blue sclerae (not deep blue) 4. Absence of dentinogenesis imperfecta 5. Absence of sensorineural hearing loss 6. Very short stature 7. Elevated serum alkaline phosphatase (in childhood) 8. Histological fish-scale lamellar pattern on bone biopsy under polarized light

After 2011, genetic confirmation by SERPINF1 sequencing or serum PEDF measurement became the gold-standard confirmatory test, superseding bone biopsy for most cases.

Laboratory Tests

Bone Biopsy (Histopathology)

• Iliac crest bone biopsy under tetracycline double-labeling reveals:
• Increased osteoid thickness
• Prolonged osteoid maturation time (increased mineral lag time)
• Fish-scale lamellar pattern under polarized light (irregularly alternating bright/dark lamellae with rotational disorder)
• Increased osteocyte density
• Decreased mineralized bone volume per tissue volume
• HP:0011001 (Increased bone mineral density) does not apply; rather HP:0004349 (Decreased bone mineral density) combined with unique histology

Genetic Testing

• First-line: Next-generation sequencing gene panel including SERPINF1 (along with other AR-OI genes: CRTAP, LEPRE1/P3H1, PPIB, SERPINH1, FKBP10, SP7, TMEM38B, SEC24D, etc.)
• Whole-exome sequencing (WES): Recommended for atypical presentations; identifies cryptic splice variants (PMC6124173)
• Whole-genome sequencing (WGS): Can detect deep intronic variants and complex structural variants if panel/WES non-diagnostic
• Single-gene Sanger sequencing: Used for targeted confirmation of identified variants; for family screening of known mutations
• Molecular confirmation is essential: the fish-scale biopsy pattern, while characteristic, requires expertise and is increasingly replaced by genetic/PEDF testing

Differential Diagnosis

11. Outcome / Prognosis

Long-Term Course

OI type VI follows a severe-to-very severe progressive course, with cumulative fractures and skeletal deformities. In the largest published follow-up cohort, all patients sustained progressive deformities despite intervention; complete cessation of fractures was not achieved (PMID:28689307).

Key outcome data from published series: - Fracture burden: 0.8–8.69 fractures/year across patients; cumulative lifetime fractures 12–200 (PMC12250282) - Mobility: All patients in one series lost independent ambulation; functional stabilization achievable with aggressive pharmacotherapy - Height: Final height severely reduced (Z-scores −2.7 to −7.7 SD); some height gain with denosumab treatment (5–8 cm over 2 years, PMC4180531) - Vertebral morphology: Vertebral reshaping and improvement in BMD with denosumab; lumbar spine BMD Z-score improves with treatment (PMID:28689307) - Life expectancy: Likely near-normal in adults receiving appropriate care (no specific mortality data published; severe early cases with thoracic restriction may be at respiratory risk)

Complications

• Respiratory failure from thoracic deformity/kyphoscoliosis (potentially fatal in severe cases)
• Spinal cord compression from severe kyphoscoliosis
• Immobility and wheelchair dependence
• Chronic pain
• Rebound hypercalcemia from denosumab discontinuation (important iatrogenic risk)

Prognostic Factors

• Variant type: Null alleles (NMD) = severest; missense alleles may have marginally different phenotypic spectrum
• Response to denosumab: Superior to bisphosphonates; BMD and fracture rates improved in all treated patients (PMC4180531; PMC6751648)
• Age at treatment initiation: Earlier treatment may prevent progressive deformity

12. Treatment

1. Bisphosphonates (Limited Efficacy)

Cyclic intravenous pamidronate (standard of care for other OI types) shows limited efficacy in OI6. Proposed mechanism: unmineralized osteoid prevents bisphosphonate binding to bone mineral (hydroxyapatite), reducing drug deposition and anti-resorptive effect (ScienceDirect, Moffatt 2006). Patients show modest increases in lumbar BMD but suboptimal fracture reduction compared to types III/IV OI.

• MAXO: MAXO:0000950 (supportive care as baseline)
• Route: IV infusions, typically q3–4 months

2. Denosumab (Anti-RANKL) — Preferred Treatment

Denosumab (NCIT:C66871; a RANKL-inhibiting monoclonal antibody) directly addresses the OI6 pathomechanism (excess RANKL-driven bone resorption due to absent PEDF). This therapeutic rationale was translated successfully by Hoyer-Kuhn et al. (PMC4180531).

Dosing: - 1 mg/kg body weight subcutaneous injection - Initial interval: 12 weeks; shortened to minimum 10 weeks if bone resorption markers re-elevate or bone pain recurs - Calcium supplementation: 500–1000 mg/day for 2 weeks post-injection - Vitamin D: Throughout treatment

Outcomes after 2 years (n=4, PMC4180531): - Continuous areal BMD increase at lumbar spine and total body - Vertebral morphology improvement (re-shaping) - Fracture rate: 0–2 fractures per patient over 2 years (vs. historical fracture burden) - Mobility improvement (BAMF and GMFM scores) - Height gain of 5–8 cm

Safety: Mild hypocalcemia post-injection managed with supplementation; no severe adverse events reported.

⚠️ Important warning: Abrupt denosumab discontinuation causes rebound hypercalcemia and rapid bone loss (rebound phenomenon); transition to bisphosphonates or gradual dose spacing is necessary.

• MAXO term: MAXO:0000950 (pharmacotherapy)
• Treatment term: NCIT:C15986 (Pharmacotherapy)
• Therapeutic agent: NCIT:C66871 (Denosumab)

3. Surgical and Orthopedic Interventions

• Intramedullary rod fixation (telescoping rods): Performed at multiple sites (femur, tibia, humerus) to stabilize deformed long bones; prevents further deformity from fractures. Multiple surgeries typically required.
• Corrective osteotomy: Realignment of severely deformed long bones; combined with rod insertion.

• Spinal stabilization: Surgical spinal fusion for severe progressive kyphoscoliosis (typically deferred until puberty)

• MAXO: MAXO:0000004 (surgical procedure)

• NCIT: NCIT:C16186 (Orthopedic Surgical Procedure)

4. Physical and Rehabilitative Therapy

• Physical therapy (MAXO:0000011): Strengthening, gait training, pool therapy (hydrotherapy preferred to minimize fracture risk)
• Occupational therapy: Adaptive equipment; mobility aids
• Pain management: analgesics, anti-inflammatory agents (used cautiously given fracture and GI risk)

5. Calcium and Vitamin D Supplementation

• Essential adjunct to all pharmacotherapy, particularly denosumab
• Targets: Serum 25-OH-D >30 ng/mL; adequate dietary calcium intake

6. Experimental / Emerging Treatments

13. Prevention

Genetic Counseling (Primary Prevention)

• Carrier testing is recommended for:
• Parents of an affected child (confirmed obligate carriers if both parents are present and healthy)
• Siblings of affected individuals (50% carrier probability)
• Members of high-risk founder populations (e.g., Tuvan population)
• Recurrence risk: 25% per pregnancy for carrier couples
• Preconception counseling: Especially in consanguineous families and founder populations

Prenatal Diagnosis

• Chorionic villus sampling (CVS) or amniocentesis: Fetal DNA tested for known parental SERPINF1 mutations after the first affected child is identified
• Preimplantation genetic testing (PGT): PGT-M (for monogenic disease) can be offered to carrier couples undergoing IVF, enabling selection of unaffected embryos

Tertiary Prevention (Complication Prevention in Affected Individuals)

• Anti-resorptive therapy (denosumab) as early as feasible to reduce fracture burden
• Calcium and vitamin D sufficiency maintained throughout life
• Safe exercise programs: Hydrotherapy, swimming — minimize high-impact loading
• Fall prevention: Adaptive mobility aids; safe home environments
• Spinal monitoring: Annual radiographs; early referral to spine surgery if progressive scoliosis
• Respiratory surveillance: Pulmonary function tests in patients with severe thoracic deformity
• Vitamin D monitoring (avoid deficiency, which worsens the mineralization defect)

Screening

• Newborn/infant screening: No population-level newborn screening for OI6 exists. Clinical suspicion arises from fractures in early infancy; SERPINF1 sequencing or serum PEDF can confirm.
• Cascade family testing: All first-degree relatives of affected individuals should be offered carrier testing if proband mutations are known.

14. Other Species / Natural Disease

Model Organisms

Serpinf1−/− Mouse (Primary Model)

The Pedf-null mouse (Serpinf1−/−) is the principal and best-validated animal model of OI type VI (Bogan et al. 2013, PMID:23413146).

Limitations: The Pedf-null mouse has a milder skeletal phenotype than most OI6 human patients. No spontaneous fractures at birth are seen (consistent with human presentation). The mouse does not fully recapitulate the extent of spinal and long-bone deformity seen in severely affected children.

• NCBI Taxon: 10090 (Mus musculus)
• Model type: Knockout (germline null)

Zebrafish

Zebrafish (Danio rerio) models of mineralization defects have been used for OI research broadly (including the chihuahua model), but serpinf1-specific zebrafish models are not prominently described in the published literature. PEDF is conserved in zebrafish.

• NCBI Taxon: 7955 (Danio rerio)

In Vitro Models

• MC3T3-E1 murine osteoblast cell line: Used to validate SERPINF1 missense mutations and ER retention phenotype (ER stress studies, 2025)
• Human bone marrow mesenchymal stem cells (hMSCs): Used to study PEDF-Wnt3a axis and mineralization; PEDF restoration improved mineralization in hMSC culture (PMC4970601)
• Primary osteoblasts from Pedf-null mice: Enhanced alizarin-red staining and elevated mineral:matrix ratio in culture (paradoxical increase in vitro, contrasting with in vivo hypomineralization, reflecting complex regulation)

15. Summary of Key Ontology Terms

HPO Phenotype Terms

GO Biological Processes

CL Cell Ontology Terms

CHEBI / Drug Terms

MAXO Treatment Terms

Key References

Sources

• Molecular and Clinical Aspects of OI Type VI — MDPI/PMC 2025 (PMC12250282)
• OMIM Entry #613982 — Osteogenesis Imperfecta Type VI
• Mutations in SERPINF1 Cause OI Type VI — PubMed PMID:21826736
• Two Years' Experience with Denosumab for Children with OI Type VI — PMC4180531
• Individualized Denosumab Treatment Follow-up — PMC6751648
• A Mouse Model for Human OI Type VI — PMC3688658
• PEDF Restoration Increases Bone Mass via Wnt3a Blockade — PMC4970601
• OI Mechanisms and Signaling Pathways Review — PMC8755987
• Update on Genetics of OI — PMC11607015
• SERPINF1 Variants in Indian OI Patients — PMC10323215
• PEDF Regulates Osteoclasts via OPG and RANKL — PubMed PMID:19945427
• PEDF Regulates SOST/Sclerostin via ERK/GSK-3β — PubMed PMID:30076958
• PEDF Reduces SOST Expression in Bone Explants — PubMed PMID:30607618
• Antagonism Between PEDF and TGF-β in OI6 — PMC11152058
• Unique Micro- and Nano-Scale Mineralization Pattern in OI6 — PubMed PMID:25554599
• Whole-Exome Sequencing Identifies Cryptic Splice Site in SERPINF1 — PMC6124173
• Osteogenesis Imperfecta — Endotext/NIH Bookshelf
• Osteogenesis Imperfecta — StatPearls/NIH Bookshelf
• NIH Genetic Testing Registry — OI Type VI
• Endoplasmic Reticulum Stress and Autophagy in SERPINF1-Induced OI6 — ScienceDirect 2025
• In-frame SERPINF1 Mutations in OI Type VI — PubMed PMID:25868797
• OI Type VI: A Form of Brittle Bone Disease with Mineralization Defect — JBMR 2002 (Glorieux)
• Setrusumab for OI — Phase 2b ASTEROID Study — JBMR 2024