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Osteogenesis Imperfecta Type III

Disease Pathophysiology Research Report

2026-02-04
Falcon MONDO:0009804 Model: Edison Scientific Literature 27 citations

Disease Pathophysiology Research Report

Target Disease - Disease Name: Osteogenesis Imperfecta Type III (progressively deforming OI) - MONDO ID: not specified by source; entry pertains to Mendelian OI classified by Sillence and modern dyadic nosology (sillence2024adyadicnosology pages 11-12). - Category: Mendelian

  1. Core Pathophysiology Osteogenesis imperfecta (OI) Type III is a severe, progressively deforming phenotype characterized by early and recurrent fractures, extreme short stature, and skeletal deformity. Mechanistically, OI across types is predominantly a collagen type I disorder; “approximately 80–85%” of OI (types I–IV) arises from autosomal-dominant COL1A1/COL1A2 mutations that alter the Gly–X–Y triple helix, perturbing folding, post-translational modifications (PTMs), and fibrillogenesis (Sun 2024, ACS Pharmacol Transl Sci, Jan 2024; DOI: 10.1021/acsptsci.3c00324) (sun2024emerginglandscapeof pages 3-4). Type III severity also results from recessive disruptions of the ER-based prolyl 3-hydroxylation/folding complex (P3H1/LEPRE1, CRTAP, PPIB), ER chaperones (SERPINH1/HSP47, FKBP10/FKBP65), ER Ca2+ homeostasis (TMEM38B/TRIC-B), transcriptional regulators of osteoblast differentiation (SP7/Osterix, CREB3L1/OASIS), and WNT1 signaling, as well as extracellular processing (BMP1), cross-linking (PLOD2), and mineralization regulators (SERPINF1/PEDF, IFITM5) (Sun 2024; Sillence 2024, Calcif Tissue Int, Jun 2024; DOI: 10.1007/s00223-024-01248-7) (sun2024emerginglandscapeof pages 2-3, sun2024emerginglandscapeof pages 3-4, sun2024emerginglandscapeof pages 5-6, sun2024emerginglandscapeof pages 6-7, sillence2024adyadicnosology pages 9-11, sun2024emerginglandscapeof pages 4-5, sillence2024adyadicnosology pages 17-18).
  2. Collagen I misfolding and PTM disruption: Gly substitutions in COL1A1/COL1A2 disrupt helix folding and the timing/extent of proline/lysine hydroxylation and glycosylation during ER assembly, driving matrix weakness and deformity (Sun 2024, Jan 2024; 10.1021/acsptsci.3c00324) (sun2024emerginglandscapeof pages 3-4).
  3. Loss of P3H1–CRTAP–PPIB complex: This ER heterotrimer catalyzes 3-hydroxylation at conserved collagen sites (e.g., Pro986 in α1(I)); loss delays triple-helix formation, leads to excessive alternative modifications, and produces severe growth deficiency and deforming phenotypes consistent with Type III (Sun 2024, Jan 2024; Sillence 2024, Jun 2024; 10.1021/acsptsci.3c00324; 10.1007/s00223-024-01248-7) (sun2024emerginglandscapeof pages 5-6, sillence2024adyadicnosology pages 9-11, sun2024emerginglandscapeof pages 4-5).
  4. ER chaperone and trafficking defects: SERPINH1/HSP47 and FKBP10/FKBP65 prevent premature protofibril formation and guide procollagen trafficking; mutations cause “misfolded pre‑collagen molecules,” alter lysine hydroxylation and cross-linking via PLOD2, and reduce collagen assembly (Sun 2024, Jan 2024; 10.1021/acsptsci.3c00324) (sun2024emerginglandscapeof pages 5-6, sun2024emerginglandscapeof pages 6-7, sillence2024adyadicnosology pages 17-18).
  5. ER Ca2+ dysregulation and ER stress: TMEM38B/TRIC-B controls ER Ca2+ flux; loss reduces Ca2+-dependent PTMs, impairs MSC→osteoblast differentiation, and provokes ER stress, compromising osteoblast function (Sun 2024, Jan 2024; 10.1021/acsptsci.3c00324) (sun2024emerginglandscapeof pages 5-6, sun2024emerginglandscapeof pages 6-7).
  6. Impaired osteoblast differentiation and signaling: SP7 and CREB3L1 regulate osteoblast maturation and collagen expression; WNT1 and MESD (LRP5/6 chaperone) affect canonical WNT/β-catenin signaling in osteoblasts. Disruption in these pathways reduces bone formation and contributes to growth failure and deformity (Sun 2024, Jan 2024; 10.1021/acsptsci.3c00324) (sun2024emerginglandscapeof pages 3-4, sun2024emerginglandscapeof pages 6-7).

  7. Extracellular processing and mineralization: BMP1 defects impair C-propeptide processing and can cause abnormal mineralization (including hypermineralization). SERPINF1 (PEDF) loss leads to mineralization defects (Type VI OI), and IFITM5 mutations impair PEDF secretion and mineralization, collectively linking matrix processing/mineralization defects to severe fragility (Sun 2024, Jan 2024; 10.1021/acsptsci.3c00324) (sun2024emerginglandscapeof pages 4-5, sun2024emerginglandscapeof pages 6-7). These mechanisms converge in osteoblasts and bone matrix to produce the severe deforming phenotype and extreme short stature typical of Type III (Sun 2024, Jan 2024; Sillence 2024, Jun 2024; 10.1021/acsptsci.3c00324; 10.1007/s00223-024-01248-7) (sun2024emerginglandscapeof pages 2-3, sillence2024adyadicnosology pages 9-11).

  8. Key Molecular Players, Cell Types, and Anatomical Sites (ontology-annotated)

  9. Principal genes/proteins: COL1A1, COL1A2; ER folding/PTM complex (CRTAP, P3H1/LEPRE1, PPIB); ER chaperones (SERPINH1/HSP47, FKBP10/FKBP65, KDELR2); cross-linking/mineralization/processing (PLOD2, BMP1, SERPINF1/PEDF, IFITM5); osteoblast differentiation/signaling (WNT1, SP7, CREB3L1/OASIS, MESD); ER Ca2+ homeostasis (TMEM38B/TRIC-B) (Sun 2024; Sillence 2024) (sun2024emerginglandscapeof pages 3-4, sun2024emerginglandscapeof pages 5-6, sun2024emerginglandscapeof pages 6-7, sillence2024adyadicnosology pages 9-11, sun2024emerginglandscapeof pages 4-5, sillence2024adyadicnosology pages 17-18).
  10. Chemical entities: antiresorptives (bisphosphonates such as pamidronate/zoledronate) widely used in severe OI; sclerostin-pathway biologics under investigation (e.g., romosozumab pediatric Phase 1 completed; NCT04545554) (Sillence 2024, Hald 2024; ClinicalTrials.gov) (sillence2024adyadicnosology pages 9-11, hald2024osteogenesisimperfectaskeletal pages 11-12).
  11. Cell types: osteoblasts (collagen I synthesis; ER stress/UPR), osteocytes (matrix-embedded mechanosensors), osteoclasts (resorption; coupling imbalance), MSCs (impaired osteogenic differentiation with ER Ca2+ defects) (Sun 2024; Hald 2024) (sun2024emerginglandscapeof pages 3-4, hald2024osteogenesisimperfectaskeletal pages 11-12).
  12. Anatomical locations: long-bone cortex, vertebral bodies (load-bearing, deformity-prone), growth plate (linear growth failure), aortic root and cardiac valves (extraskeletal collagen I tissues with reported abnormalities) (Sillence 2024; Hald 2024; Verdonk 2024) (sillence2024adyadicnosology pages 11-12, hald2024osteogenesisimperfectaskeletal pages 11-12, verdonk2024isosteogenesisimperfecta pages 1-2).

The following structured table provides ontology-aligned details for knowledge-base ingestion and references.

Table (click to expand)
Category Name Ontology Identifier Mechanistic role in OI Type III Supporting source (DOI/URL) Year
Gene/Protein COL1A1 HGNC HGNC:COL1A1 Gly-X-Y Gly substitutions in the α1(I) chain disrupt triple-helix folding, alter PTMs and fibrillogenesis causing severe/deforming phenotype https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 3-4, sillence2024adyadicnosology pages 9-11) 2024
Gene/Protein COL1A2 HGNC HGNC:COL1A2 Mutations in α2(I) chain cause helix instability and genotype–phenotype correlation with severe forms (type III) https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 3-4, sillence2024adyadicnosology pages 9-11) 2024
Gene/Protein CRTAP HGNC HGNC:CRTAP Component of P3H1–CRTAP–PPIB complex; loss → defective prolyl 3-hydroxylation, delayed helix folding, severe recessive OI https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 5-6, sillence2024adyadicnosology pages 9-11) 2024
Gene/Protein LEPRE1 (P3H1) HGNC HGNC:LEPRE1 Prolyl 3-hydroxylase (P3H1); required for Pro986 3-hydroxylation of α1(I); loss causes severe growth deficiency and deforming phenotype https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 5-6, sillence2024adyadicnosology pages 9-11) 2024
Gene/Protein PPIB (CyPB) HGNC HGNC:PPIB Cyclophilin B; part of 3-hydroxylation complex; mutations disrupt complex and collagen PTMs → severe OI https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 5-6) 2024
Gene/Protein SERPINH1 (HSP47) HGNC HGNC:SERPINH1 ER chaperone HSP47; mutations → misfolded procollagen and trafficking defects, contributing to severe phenotype https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 5-6, sun2024emerginglandscapeof pages 6-7) 2024
Gene/Protein FKBP10 (FKBP65) HGNC HGNC:FKBP10 ER peptidyl-prolyl isomerase; loss alters lysine hydroxylation (PLOD2 activity) and collagen cross-linking → deformity https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 5-6, sun2024emerginglandscapeof pages 6-7) 2024
Gene/Protein PLOD2 HGNC HGNC:PLOD2 Lysyl hydroxylase (telopeptide hydroxylation) required for correct collagen cross-links; defects cause progressive deforming phenotypes https://doi.org/10.1021/acsptsci.3c00324, https://doi.org/10.1007/s00223-024-01248-7 (sun2024emerginglandscapeof pages 3-4, sillence2024adyadicnosology pages 9-11) 2024
Gene/Protein BMP1 HGNC HGNC:BMP1 C-propeptide processing metalloprotease; mutations alter procollagen processing and can produce abnormal mineralization/hypermineralization https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 6-7, sillence2024adyadicnosology pages 16-17) 2024
Gene/Protein WNT1 HGNC HGNC:WNT1 Canonical WNT/β-catenin signaling regulator of osteoblast differentiation; mutations reduce bone formation and contribute to severe OI https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 3-4, sun2024emerginglandscapeof pages 6-7) 2024
Gene/Protein SP7 (Osterix) HGNC HGNC:SP7 Transcription factor required for pre-osteoblast → osteoblast maturation; loss impairs osteoblast differentiation and bone formation https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 3-4, sun2024emerginglandscapeof pages 5-6) 2024
Gene/Protein CREB3L1 (OASIS) HGNC HGNC:CREB3L1 ER-to-nucleus transcription factor (RIP-activated) regulating osteoblast genes; mutations linked to severe osteodysplasia and reduced collagen https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 6-7) 2024
Gene/Protein TMEM38B (TRIC-B) HGNC HGNC:TMEM38B ER ion channel regulating ER Ca2+ homeostasis; loss → impaired Ca2+-dependent PTMs, ER stress, reduced MSC→osteoblast differentiation https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 5-6, sun2024emerginglandscapeof pages 6-7) 2024
Gene/Protein SERPINF1 (PEDF) HGNC HGNC:SERPINF1 Secreted PEDF influences osteoblast mineralization; recessive loss (type VI) causes mineralization defects and fragility https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 4-5) 2024
Gene/Protein IFITM5 HGNC HGNC:IFITM5 BRIL protein; pathogenic mutations alter palmitoylation/Golgi localization, impair PEDF secretion and osteoblast mineralization https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 4-5) 2024
Gene/Protein KDELR2 HGNC HGNC:KDELR2 ER retrieval receptor; mutations mislocalize HSP47 and reduce HSP47/FKBP65 levels → impaired collagen assembly https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 6-7) 2024
Gene/Protein MESD HGNC HGNC:MESD ER chaperone for LRP5/6 trafficking; loss impairs WNT receptor trafficking and downstream osteoblast signaling https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 6-7) 2024
Biological Process Collagen fibril organization GO GO: collagen fibril organization Disrupted fibrillogenesis from misfolded collagen and altered cross-linking underlies bone fragility and deformity https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 3-4) 2024
Biological Process Prolyl 3-hydroxylation GO GO: prolyl 3-hydroxylation P3H1–CRTAP–PPIB complex normally 3‑hydroxylates Pro986; loss → defective helix stability and severe OI https://doi.org/10.1021/acsptsci.3c00324, https://doi.org/10.1007/s00223-024-01248-7 (sun2024emerginglandscapeof pages 5-6, sillence2024adyadicnosology pages 9-11) 2024
Biological Process ER protein folding / chaperone activity GO GO: ER protein folding HSP47, FKBP65, CyPB and others ensure procollagen folding; defects produce ER retention/misfolding and UPR/functional osteoblast impairment https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 5-6, sun2024emerginglandscapeof pages 3-4) 2024
Biological Process Unfolded Protein Response (UPR) GO GO: UPR / ER stress response Chronic ER stress from misfolded collagen perturbs osteoblast survival/function contributing to severe phenotype https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 5-6) 2024
Biological Process ER calcium homeostasis GO GO: ER calcium homeostasis TMEM38B/TRIC-B defects alter Ca2+ flux, impair Ca2+-dependent PTMs and osteoblast differentiation → skeletal deformity https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 5-6, sun2024emerginglandscapeof pages 6-7) 2024
Biological Process Osteoblast differentiation (WNT/β‑catenin) GO GO: osteoblast differentiation WNT1, MESD, SP7 and CREB3L1 disruption reduce osteoblast maturation and matrix production causing growth deficiency https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 3-4, sun2024emerginglandscapeof pages 6-7) 2024
Biological Process Extracellular matrix organization GO GO: extracellular matrix organization Abnormal collagen secretion/processing (BMP1, cross‑linking defects) alters ECM structure and mechanical properties https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 6-7, sillence2024adyadicnosology pages 16-17) 2024
Biological Process Collagen cross-linking GO GO: collagen cross-linking PLOD2 and FKBP10 influence telopeptide hydroxylation and cross-links; defects → weak matrix and progressive deformity https://doi.org/10.1021/acsptsci.3c00324, https://doi.org/10.1007/s00223-024-01248-7 (sun2024emerginglandscapeof pages 6-7, sillence2024adyadicnosology pages 9-11) 2024
Biological Process Mineralization GO GO: biomineralization / mineralization SERPINF1, IFITM5, BMP1 and abnormal collagen affect mineral deposition, sometimes causing hypomineralization or paradoxical hypermineralization https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 4-5, sun2024emerginglandscapeof pages 6-7) 2024
Cellular Component Endoplasmic reticulum (ER) GO GO: endoplasmic reticulum Site of procollagen folding, PTMs and chaperone engagement; central locus of pathology in many Type III cases https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 3-4, sun2024emerginglandscapeof pages 5-6) 2024
Cellular Component ER–Golgi intermediate compartment GO GO: ER–Golgi intermediate compartment Important for procollagen trafficking; perturbation (e.g., KDELR2) alters secretion and assembly https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 6-7) 2024
Cellular Component Extracellular matrix / collagen fibril GO GO: extracellular matrix / collagen fibril Final location of collagen; defective assembly yields mechanically weak fibrils and bone fragility https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 3-4) 2024
Cellular Component Golgi apparatus GO GO: Golgi apparatus Site for glycosylation/processing of collagen; IFITM5 Golgi sequestration noted to impair osteoblast function https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 4-5) 2024
Cell Type Osteoblast CL CL:0000189 (osteoblast) Primary collagen-producing bone cell; ER stress and impaired differentiation in osteoblasts drive Type III severity https://doi.org/10.1021/acsptsci.3c00324, https://doi.org/10.1007/s00223-024-01236-x (sun2024emerginglandscapeof pages 3-4, hald2024osteogenesisimperfectaskeletal pages 11-12) 2024
Cell Type Osteocyte CL CL:0001989 (osteocyte) Embedded bone cell influenced by altered matrix; contributes to bone remodeling signaling imbalance https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 3-4) 2024
Cell Type Osteoclast CL CL:0000653 (osteoclast) Resorptive cell; osteoblast–osteoclast imbalance affects net bone mass and deformity risk https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 3-4) 2024
Cell Type Bone marrow stromal cell (MSC) CL CL:0000711 (MSC) MSC differentiation into osteoblasts is impaired by ER Ca2+ dysregulation and signaling defects (TMEM38B, WNT pathway) https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 5-6) 2024
Anatomical Location Bone cortex (long bone) UBERON UBERON:0005924 (long bone cortex) Principal load‑bearing tissue where abnormal collagen fibrils cause fragility, deformity and fractures (Type III pronounced) https://doi.org/10.1021/acsptsci.3c00324, https://doi.org/10.1007/s00223-024-01248-7 (sun2024emerginglandscapeof pages 3-4, sillence2024adyadicnosology pages 9-11) 2024
Anatomical Location Growth plate UBERON UBERON:0002081 (growth plate) Disrupted collagen/osteoblast function leads to impaired linear growth and extreme short stature in Type III https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 2-3) 2024
Anatomical Location Vertebral body UBERON UBERON:0002105 (vertebral body) Prone to compression fractures and progressive kyphoscoliosis in severe/deforming OI https://doi.org/10.1007/s00223-024-01236-x (hald2024osteogenesisimperfectaskeletal pages 11-12, hald2024osteogenesisimperfectaskeletal pages 1-3) 2024
Anatomical Location Aortic root UBERON UBERON:0004217 (aortic root) Collagen I present in cardiovascular ECM; OI-associated valvular/aortic root abnormalities reported (extraskeletal involvement) https://doi.org/10.1007/s00223-023-01171-3 (verdonk2024isosteogenesisimperfecta pages 1-2) 2024
Chemical/Drug Bisphosphonates (pamidronate, zoledronate) CHEBI CHEBI:23688 (bisphosphonate class) Anti-resorptive therapy widely used to reduce fracture rates and improve mobility in severe OI; long-term adult effects under study https://doi.org/10.1007/s00223-024-01248-7, https://doi.org/10.1007/s00223-024-01236-x (sillence2024adyadicnosology pages 9-11, hald2024osteogenesisimperfectaskeletal pages 11-12) 2024
Chemical/Drug Sclerostin pathway agents (e.g., romosozumab class) CHEBI CHEBI: not specific (sclerostin antibody class) Anabolic/sclerostin-targeting approaches are under investigation to increase bone formation in OI (clinical studies ongoing) NCT04545554 (romosozumab pediatric study) and reviews https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 18-18, sun2024emerginglandscapeof pages 3-4) 2024

Table: Concise ontology‑annotated table mapping genes, processes, components, cell types, anatomical sites and therapies implicated in Osteogenesis Imperfecta Type III, with mechanistic roles and 2023–2024 supporting sources (context IDs). This table is designed for knowledge‑base annotation and rapid reference.

  1. Biological Processes (candidate GO annotations)

  2. Collagen fibril organization; extracellular matrix organization; collagen biosynthetic process; prolyl 3-hydroxylation; collagen cross-linking; ER protein folding; ER Ca2+ homeostasis; unfolded protein response; osteoblast differentiation (WNT/β-catenin); bone mineralization (Sun 2024; Sillence 2024) (sun2024emerginglandscapeof pages 3-4, sun2024emerginglandscapeof pages 5-6, sillence2024adyadicnosology pages 9-11, sun2024emerginglandscapeof pages 4-5).

  3. Cellular Components

  4. Endoplasmic reticulum; ER–Golgi intermediate compartment; Golgi apparatus; extracellular matrix and collagen fibril; osteoblast/osteocyte lacuno-canalicular system (Sun 2024; Sillence 2024) (sun2024emerginglandscapeof pages 3-4, sun2024emerginglandscapeof pages 5-6, sillence2024adyadicnosology pages 9-11).

  5. Disease Progression: Sequence of Events

  6. Initiation: Genetic variants affecting collagen I (COL1A1/COL1A2) or collagen processing/folding (CRTAP, P3H1, PPIB; SERPINH1/FKBP10; TMEM38B; BMP1; PLOD2) or osteoblast signaling/differentiation (WNT1, SP7, CREB3L1) (Sun 2024; Sillence 2024) (sun2024emerginglandscapeof pages 3-4, sillence2024adyadicnosology pages 9-11).
  7. Cellular dysfunction: Misfolded collagen and delayed helix formation; abnormal PTMs and cross-linking; ER retention and ER stress/UPR; reduced osteoblast differentiation and ECM production; aberrant mineralization (Sun 2024, Jan 2024; 10.1021/acsptsci.3c00324) (sun2024emerginglandscapeof pages 5-6, sun2024emerginglandscapeof pages 6-7, sun2024emerginglandscapeof pages 4-5).
  8. Tissue-level consequences: Weak collagen fibrils and disorganized ECM lead to frequent fractures, vertebral compression, progressive deformity, and growth plate dysfunction with extreme short stature—defining the Type III phenotype (Sillence 2024, Jun 2024; 10.1007/s00223-024-01248-7) (sillence2024adyadicnosology pages 11-12, sillence2024adyadicnosology pages 9-11).
  9. Systemic/extra-skeletal: Collagen I defects extend to cardiovascular tissues; a systematic review found “valvular disease, heart failure, atrial fibrillation, and hypertension” more prevalent in OI, with “a larger aortic root” vs controls; abnormalities occur “in all types of OI and at all ages,” though progression is unclear (Verdonk 2024, Jan 2024; 10.1007/s00223-023-01171-3) (verdonk2024isosteogenesisimperfecta pages 1-2).

  10. Modern outcomes: Historically high pediatric respiratory mortality in severe OI has been markedly reduced with multidisciplinary care and cyclic IV bisphosphonates (pre-bisphosphonate era estimate: “60% of children died from respiratory failure before their 18th birthday”) (Sillence 2024, Jun 2024; 10.1007/s00223-024-01248-7) (sillence2024adyadicnosology pages 11-12).

  11. Phenotypic Manifestations and Clinical Correlates

  12. Core skeletal: Severe, progressively deforming bone disease with recurrent fractures, extreme short stature, and kyphoscoliosis/vertebral compression (Sillence 2024; Hald 2024) (sillence2024adyadicnosology pages 11-12, hald2024osteogenesisimperfectaskeletal pages 11-12).
  13. Spine and joints: Scoliosis reported in 26–76% across ages; ligament laxity and early osteoarthritis contribute to pain and disability (Hald 2024, Jun 2024; 10.1007/s00223-024-01236-x) (hald2024osteogenesisimperfectaskeletal pages 3-4, hald2024osteogenesisimperfectaskeletal pages 8-10).
  14. Extraskeletal: Hearing loss, dental anomalies (dentinogenesis imperfecta), ocular signs (blue sclerae), cardiopulmonary involvement likely beyond skeletal deformity effects (Hald 2024; Verdonk 2024) (hald2024osteogenesisimperfectaskeletal pages 11-12, verdonk2024isosteogenesisimperfecta pages 1-2).
  15. Patient-reported burden and adult outcomes: Cross-sectional data report 41.8% chronic pain and ~65% at least moderate fatigue; health-related quality of life reduction is mainly physical; median lifespan 72.4 years (men) and 77.4 years (women) (Hald 2024, Jun 2024; 10.1007/s00223-024-01236-x) (hald2024osteogenesisimperfectaskeletal pages 6-8, hald2024osteogenesisimperfectaskeletal pages 1-3).

Expert Opinions and 2023–2024 Reviews - Dyadic nosology emphasizes pairing genotype with Sillence phenotypes to reflect matrix biology and genomic complexity (>40 OI/bone fragility genes), providing a modern classification framework (Sillence 2024, Jun 2024; 10.1007/s00223-024-01248-7) (sillence2024adyadicnosology pages 11-12). - Contemporary adult-focused review argues OI is a systemic disease with significant adult musculoskeletal and extraskeletal morbidity and calls for longitudinal registries to define cardiovascular and other risks (Hald 2024, Jun 2024; 10.1007/s00223-024-01236-x) (hald2024osteogenesisimperfectaskeletal pages 1-3, hald2024osteogenesisimperfectaskeletal pages 11-12, hald2024osteogenesisimperfectaskeletal pages 6-8). - Mechanistic synthesis (Sun 2024) highlights convergence of collagen I misfolding, ER proteostasis (folding/PTMs, Ca2+ homeostasis), extracellular processing/cross-linking, and osteoblast differentiation signaling (WNT1/SP7/CREB3L1) as drivers of severe deforming phenotypes with growth deficiency (Sun 2024, Jan 2024; 10.1021/acsptsci.3c00324) (sun2024emerginglandscapeof pages 18-18, sun2024emerginglandscapeof pages 6-7, sun2024emerginglandscapeof pages 5-6, sun2024emerginglandscapeof pages 3-4). - Cardiovascular systematic review recommends “low-threshold” cardiology referral given increased prevalence of valvular disease, heart failure, AF, hypertension, and larger aortic root, but notes lack of longitudinal progression data (Verdonk 2024, Jan 2024; 10.1007/s00223-023-01171-3) (verdonk2024isosteogenesisimperfecta pages 1-2).

Current Applications and Real-world Implementations - Pharmacologic: Cyclic IV bisphosphonates remain standard in severe pediatric OI within multidisciplinary programs, improving mobility and survival (Sillence 2024, Jun 2024; Hald 2024, Jun 2024) (sillence2024adyadicnosology pages 11-12, hald2024osteogenesisimperfectaskeletal pages 11-12). Adult long-term effects and antifracture efficacy remain under evaluation (Hald 2024) (hald2024osteogenesisimperfectaskeletal pages 3-4). - Anabolic/sclerostin pathway: Pediatric Phase 1 study of romosozumab in OI completed (NCT04545554; ClinicalTrials.gov), reflecting translational application of WNT pathway biology; broader efficacy/safety across subtypes (including Type III) remain areas of active research (sun2024emerginglandscapeof pages 18-18). - Multisystem care: Adult care increasingly addresses cardiopulmonary, neuromuscular, dental/oral, and women’s health domains in addition to bone, with emphasis on registries and standardized outcomes (Hald 2024; Rapoport 2023, Orphanet J Rare Dis, Feb 2023; 10.1186/s13023-023-02627-3) (hald2024osteogenesisimperfectaskeletal pages 11-12, hald2024osteogenesisimperfectaskeletal pages 8-10).

Selected Direct Quotes - “Approximately 80–85%” of OI (types I–IV) arise from autosomal‑dominant COL1A1/COL1A2 variants disrupting the triple-helix (Sun 2024, Jan 2024; 10.1021/acsptsci.3c00324) (sun2024emerginglandscapeof pages 3-4). - “Valvular disease, heart failure, atrial fibrillation, and hypertension appear to be more prevalent in OI… [and] a larger aortic root was observed in OI compared to controls” (Verdonk 2024, Jan 2024; 10.1007/s00223-023-01171-3) (verdonk2024isosteogenesisimperfecta pages 1-2). - “In the pre-bisphosphonate era, 60% of children died from respiratory failure before their 18th birthday” (Sillence 2024, Jun 2024; 10.1007/s00223-024-01248-7) (sillence2024adyadicnosology pages 11-12).

Ontology Annotations (examples) - Genes/Proteins (HGNC): COL1A1; COL1A2; CRTAP; LEPRE1/P3H1; PPIB; SERPINH1; FKBP10; PLOD2; BMP1; WNT1; SP7; CREB3L1; TMEM38B; SERPINF1; IFITM5 (sun2024emerginglandscapeof pages 3-4, sun2024emerginglandscapeof pages 5-6, sun2024emerginglandscapeof pages 6-7, sillence2024adyadicnosology pages 9-11). - Biological Processes (GO): collagen fibril organization; prolyl 3‑hydroxylation; ER protein folding; UPR; ER Ca2+ homeostasis; osteoblast differentiation (WNT/β‑catenin); ECM organization; collagen cross-linking; mineralization (sun2024emerginglandscapeof pages 3-4, sun2024emerginglandscapeof pages 5-6, sillence2024adyadicnosology pages 9-11, sun2024emerginglandscapeof pages 4-5). - Cellular Components (GO): endoplasmic reticulum; ER–Golgi intermediate compartment; Golgi apparatus; extracellular matrix/collagen fibril (sun2024emerginglandscapeof pages 3-4, sun2024emerginglandscapeof pages 5-6, sillence2024adyadicnosology pages 9-11). - Cell Types (CL): osteoblast (CL:0000189); osteocyte (CL:0001989); osteoclast (CL:0000653); bone-marrow stromal cell (CL:0000711) (sun2024emerginglandscapeof pages 3-4, hald2024osteogenesisimperfectaskeletal pages 11-12). - Anatomical Locations (UBERON): long bone cortex (UBERON:0005924); vertebral body (UBERON:0002105); growth plate (UBERON:0002081); aortic root (UBERON:0004217) (sillence2024adyadicnosology pages 11-12, hald2024osteogenesisimperfectaskeletal pages 11-12, verdonk2024isosteogenesisimperfecta pages 1-2). - Chemical Entities (CHEBI): bisphosphonates (CHEBI:23688); sclerostin‑pathway monoclonal antibodies (class) (sillence2024adyadicnosology pages 9-11, hald2024osteogenesisimperfectaskeletal pages 11-12).

References (URLs and dates) - Sun Y et al. Emerging landscape of osteogenesis imperfecta pathogenesis and therapeutic approaches. ACS Pharmacol Transl Sci. Jan 2024. https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 18-18, sun2024emerginglandscapeof pages 6-7, sun2024emerginglandscapeof pages 4-5, sun2024emerginglandscapeof pages 3-4, sun2024emerginglandscapeof pages 2-3, sun2024emerginglandscapeof pages 5-6). - Sillence DO. A Dyadic Nosology for Osteogenesis Imperfecta and Bone Fragility Syndromes 2024. Calcif Tissue Int. Jun 2024. https://doi.org/10.1007/s00223-024-01248-7 (sillence2024adyadicnosology pages 11-12, sillence2024adyadicnosology pages 9-11, sillence2024adyadicnosology pages 16-17, sillence2024adyadicnosology pages 17-18). - Hald JD et al. Osteogenesis imperfecta: skeletal and non-skeletal challenges in adulthood. Calcif Tissue Int. Jun 2024. https://doi.org/10.1007/s00223-024-01236-x (hald2024osteogenesisimperfectaskeletal pages 11-12, hald2024osteogenesisimperfectaskeletal pages 8-10, hald2024osteogenesisimperfectaskeletal pages 1-3, hald2024osteogenesisimperfectaskeletal pages 6-8, hald2024osteogenesisimperfectaskeletal pages 3-4). - Verdonk SJE et al. Is Osteogenesis Imperfecta Associated with Cardiovascular Abnormalities? Calcif Tissue Int. Jan 2024. https://doi.org/10.1007/s00223-023-01171-3 (verdonk2024isosteogenesisimperfecta pages 1-2). - Rapoport M et al. The patient clinical journey and socioeconomic impact of osteogenesis imperfecta: a systematic scoping review. Orphanet J Rare Dis. Feb 2023. https://doi.org/10.1186/s13023-023-02627-3 (hald2024osteogenesisimperfectaskeletal pages 8-10). - ClinicalTrials.gov. Study to Evaluate Romosozumab in Children and Adolescents With Osteogenesis Imperfecta (NCT04545554). Status: Completed. https://clinicaltrials.gov/study/NCT04545554 (sun2024emerginglandscapeof pages 18-18).

Limitations and evidence gaps - Quantitative measurements of ER stress/UPR activation and specific pathway fluxes in human Type III osteoblasts remain limited in 2023–2024 sources reviewed here; most evidence integrates genetic mechanisms, cellular models, and clinical correlation (Sun 2024; Hald 2024) (sun2024emerginglandscapeof pages 18-18, hald2024osteogenesisimperfectaskeletal pages 11-12). Longitudinal cardiovascular risk trajectories lack robust data, despite higher observed prevalences (Verdonk 2024) (verdonk2024isosteogenesisimperfecta pages 1-2).

References

  1. (sun2024emerginglandscapeof pages 18-18): Yu Sun, Lin Li, Jiajun Wang, Huiting Liu, and Hu Wang. Emerging landscape of osteogenesis imperfecta pathogenesis and therapeutic approaches. ACS pharmacology & translational science, 7 1:72-96, Jan 2024. URL: https://doi.org/10.1021/acsptsci.3c00324, doi:10.1021/acsptsci.3c00324. This article has 17 citations and is from a peer-reviewed journal.

  2. (sun2024emerginglandscapeof pages 3-4): Yu Sun, Lin Li, Jiajun Wang, Huiting Liu, and Hu Wang. Emerging landscape of osteogenesis imperfecta pathogenesis and therapeutic approaches. ACS pharmacology & translational science, 7 1:72-96, Jan 2024. URL: https://doi.org/10.1021/acsptsci.3c00324, doi:10.1021/acsptsci.3c00324. This article has 17 citations and is from a peer-reviewed journal.

  3. (sun2024emerginglandscapeof pages 2-3): Yu Sun, Lin Li, Jiajun Wang, Huiting Liu, and Hu Wang. Emerging landscape of osteogenesis imperfecta pathogenesis and therapeutic approaches. ACS pharmacology & translational science, 7 1:72-96, Jan 2024. URL: https://doi.org/10.1021/acsptsci.3c00324, doi:10.1021/acsptsci.3c00324. This article has 17 citations and is from a peer-reviewed journal.

  4. (hald2024osteogenesisimperfectaskeletal pages 11-12): Jannie Dahl Hald, Bente Langdahl, Lars Folkestad, Lena Lande Wekre, Riley Johnson, Sandesh C. S. Nagamani, Cathleen Raggio, Stuart H. Ralston, Oliver Semler, Laura Tosi, and Eric Orwoll. Osteogenesis imperfecta: skeletal and non-skeletal challenges in adulthood. Calcified Tissue International, 115:863-872, Jun 2024. URL: https://doi.org/10.1007/s00223-024-01236-x, doi:10.1007/s00223-024-01236-x. This article has 12 citations and is from a peer-reviewed journal.

  5. (hald2024osteogenesisimperfectaskeletal pages 8-10): Jannie Dahl Hald, Bente Langdahl, Lars Folkestad, Lena Lande Wekre, Riley Johnson, Sandesh C. S. Nagamani, Cathleen Raggio, Stuart H. Ralston, Oliver Semler, Laura Tosi, and Eric Orwoll. Osteogenesis imperfecta: skeletal and non-skeletal challenges in adulthood. Calcified Tissue International, 115:863-872, Jun 2024. URL: https://doi.org/10.1007/s00223-024-01236-x, doi:10.1007/s00223-024-01236-x. This article has 12 citations and is from a peer-reviewed journal.

  6. (verdonk2024isosteogenesisimperfecta pages 1-2): Sara J. E. Verdonk, Silvia Storoni, Dimitra Micha, Joost G. van den Aardweg, Paolo Versacci, Luca Celli, Ralph de Vries, Lidiia Zhytnik, Otto Kamp, Marianna Bugiani, and Elisabeth M. W. Eekhoff. Is osteogenesis imperfecta associated with cardiovascular abnormalities? a systematic review of the literature. Calcified Tissue International, 114:210-221, Jan 2024. URL: https://doi.org/10.1007/s00223-023-01171-3, doi:10.1007/s00223-023-01171-3. This article has 17 citations and is from a peer-reviewed journal.

  7. (hald2024osteogenesisimperfectaskeletal pages 1-3): Jannie Dahl Hald, Bente Langdahl, Lars Folkestad, Lena Lande Wekre, Riley Johnson, Sandesh C. S. Nagamani, Cathleen Raggio, Stuart H. Ralston, Oliver Semler, Laura Tosi, and Eric Orwoll. Osteogenesis imperfecta: skeletal and non-skeletal challenges in adulthood. Calcified Tissue International, 115:863-872, Jun 2024. URL: https://doi.org/10.1007/s00223-024-01236-x, doi:10.1007/s00223-024-01236-x. This article has 12 citations and is from a peer-reviewed journal.

  8. (sillence2024adyadicnosology pages 11-12): David Owen Sillence. A dyadic nosology for osteogenesis imperfecta and bone fragility syndromes 2024. Calcified Tissue International, 115:873-890, Jun 2024. URL: https://doi.org/10.1007/s00223-024-01248-7, doi:10.1007/s00223-024-01248-7. This article has 29 citations and is from a peer-reviewed journal.

  9. (sun2024emerginglandscapeof pages 5-6): Yu Sun, Lin Li, Jiajun Wang, Huiting Liu, and Hu Wang. Emerging landscape of osteogenesis imperfecta pathogenesis and therapeutic approaches. ACS pharmacology & translational science, 7 1:72-96, Jan 2024. URL: https://doi.org/10.1021/acsptsci.3c00324, doi:10.1021/acsptsci.3c00324. This article has 17 citations and is from a peer-reviewed journal.

  10. (sun2024emerginglandscapeof pages 6-7): Yu Sun, Lin Li, Jiajun Wang, Huiting Liu, and Hu Wang. Emerging landscape of osteogenesis imperfecta pathogenesis and therapeutic approaches. ACS pharmacology & translational science, 7 1:72-96, Jan 2024. URL: https://doi.org/10.1021/acsptsci.3c00324, doi:10.1021/acsptsci.3c00324. This article has 17 citations and is from a peer-reviewed journal.

  11. (sillence2024adyadicnosology pages 9-11): David Owen Sillence. A dyadic nosology for osteogenesis imperfecta and bone fragility syndromes 2024. Calcified Tissue International, 115:873-890, Jun 2024. URL: https://doi.org/10.1007/s00223-024-01248-7, doi:10.1007/s00223-024-01248-7. This article has 29 citations and is from a peer-reviewed journal.

  12. (sun2024emerginglandscapeof pages 4-5): Yu Sun, Lin Li, Jiajun Wang, Huiting Liu, and Hu Wang. Emerging landscape of osteogenesis imperfecta pathogenesis and therapeutic approaches. ACS pharmacology & translational science, 7 1:72-96, Jan 2024. URL: https://doi.org/10.1021/acsptsci.3c00324, doi:10.1021/acsptsci.3c00324. This article has 17 citations and is from a peer-reviewed journal.

  13. (sillence2024adyadicnosology pages 17-18): David Owen Sillence. A dyadic nosology for osteogenesis imperfecta and bone fragility syndromes 2024. Calcified Tissue International, 115:873-890, Jun 2024. URL: https://doi.org/10.1007/s00223-024-01248-7, doi:10.1007/s00223-024-01248-7. This article has 29 citations and is from a peer-reviewed journal.

  14. (hald2024osteogenesisimperfectaskeletal pages 3-4): Jannie Dahl Hald, Bente Langdahl, Lars Folkestad, Lena Lande Wekre, Riley Johnson, Sandesh C. S. Nagamani, Cathleen Raggio, Stuart H. Ralston, Oliver Semler, Laura Tosi, and Eric Orwoll. Osteogenesis imperfecta: skeletal and non-skeletal challenges in adulthood. Calcified Tissue International, 115:863-872, Jun 2024. URL: https://doi.org/10.1007/s00223-024-01236-x, doi:10.1007/s00223-024-01236-x. This article has 12 citations and is from a peer-reviewed journal.

  15. (sillence2024adyadicnosology pages 16-17): David Owen Sillence. A dyadic nosology for osteogenesis imperfecta and bone fragility syndromes 2024. Calcified Tissue International, 115:873-890, Jun 2024. URL: https://doi.org/10.1007/s00223-024-01248-7, doi:10.1007/s00223-024-01248-7. This article has 29 citations and is from a peer-reviewed journal.

  16. (hald2024osteogenesisimperfectaskeletal pages 6-8): Jannie Dahl Hald, Bente Langdahl, Lars Folkestad, Lena Lande Wekre, Riley Johnson, Sandesh C. S. Nagamani, Cathleen Raggio, Stuart H. Ralston, Oliver Semler, Laura Tosi, and Eric Orwoll. Osteogenesis imperfecta: skeletal and non-skeletal challenges in adulthood. Calcified Tissue International, 115:863-872, Jun 2024. URL: https://doi.org/10.1007/s00223-024-01236-x, doi:10.1007/s00223-024-01236-x. This article has 12 citations and is from a peer-reviewed journal.