Osteogenesis Imperfecta

Type I collagen (Col1) is the most abundant protein in mammals. Col1 contributes to 90% of the total organic component of bone matrix. However, the precise cellular origin and functional contribution of Col1 in embryogenesis and bone formation remain unknown. Single-cell RNA-sequencing analysis identifies Fap+ cells and Fsp1+ cells as the major contributors of Col1 in the bone. We generate transgenic mouse models to genetically delete Col1 in various cell lineages. Complete, whole-body Col1 deletion leads to failed gastrulation and early embryonic lethality. Specific Col1 deletion in Fap+ cells causes severe skeletal defects, with hemorrhage, edema, and prenatal lethality. Specific Col1 deletion in Fsp1+ cells results in Osteogenesis Imperfecta-like phenotypes in adult mice, with spontaneous fractures and compromised bone healing. This study demonstrates specific contributions of mesenchymal cell lineages to Col1 production in organogenesis, skeletal development, and bone formation/repair, with potential insights into cell-based therapy for patients with Osteogenesis Imperfecta.

BACKGROUNDCurrently, there is no disease-specific therapy for osteogenesis imperfecta (OI). Preclinical studies demonstrate that excessive TGF-β signaling is a pathogenic mechanism in OI. Here, we evaluated TGF-β signaling in children with OI and conducted a phase I clinical trial of TGF-β inhibition in adults with OI.METHODSHistology and RNA-Seq were performed on bones obtained from children. Gene Ontology (GO) enrichment assay, gene set enrichment analysis (GSEA), and Ingenuity Pathway Analysis (IPA) were used to identify dysregulated pathways. Reverse-phase protein array, Western blot, and IHC were performed to evaluate protein expression. A phase I study of fresolimumab, a TGF-β neutralizing antibody, was conducted in 8 adults with OI. Safety and effects on bone remodeling markers and lumbar spine areal bone mineral density (LS aBMD) were assessed.RESULTSOI bone demonstrated woven structure, increased osteocytes, high turnover, and reduced maturation. SMAD phosphorylation was the most significantly upregulated GO molecular event. GSEA identified the TGF-β pathway as the top activated signaling pathway, and IPA showed that TGF-β1 was the most significant activated upstream regulator mediating the global changes identified in OI bone. Treatment with fresolimumab was well-tolerated and associated with increases in LS aBMD in participants with OI type IV, whereas participants with OI type III and VIII had unchanged or decreased LS aBMD.CONCLUSIONIncreased TGF-β signaling is a driver pathogenic mechanism in OI. Anti-TGF-β therapy could be a potential disease-specific therapy, with dose-dependent effects on bone mass and turnover.TRIAL REGISTRATIONClinicalTrials.gov NCT03064074.FUNDINGBrittle Bone Disorders Consortium (U54AR068069), Clinical Translational Core of Baylor College of Medicine Intellectual and Developmental Disabilities Research Center (P50HD103555) from National Institute of Child Health and Human Development, USDA/ARS (cooperative agreement 58-6250-6-001), and Sanofi Genzyme.

Osteogenesis Imperfecta (OI) comprises a heterogeneous group of patients who share bone fragility and deformities as the main characteristics, albeit with different degrees of severity. Phenotypic variation also exists in other connective tissue aspects of the disease, complicating disease classification and disease course prediction. Although collagen type I defects are long established as the primary cause of the bone pathology, we are still far from comprehending the complete mechanism. In the last years, the advent of next generation sequencing has triggered the discovery of many new genetic causes for OI, helping to draw its molecular landscape. It has become clear that, in addition to collagen type I genes, OI can be caused by multiple proteins connected to different parts of collagen biosynthesis. The production of collagen entails a complex process, starting from the production of the collagen Iα1 and collagen Iα2 chains in the endoplasmic reticulum, during and after which procollagen is subjected to a plethora of posttranslational modifications by chaperones. After reaching the Golgi organelle, procollagen is destined to the extracellular matrix where it forms collagen fibrils. Recently discovered mutations in components of the retrograde transport of chaperones highlight its emerging role as critical contributor of OI development. This review offers an overview of collagen regulation in the context of recent gene discoveries, emphasizing the significance of transport disruptions in the OI mechanism. We aim to motivate exploration of skeletal fragility in OI from the perspective of these pathways to identify regulatory points which can hint to therapeutic targets.

This study explored whether Romosozumab, an anti-sclerostin antibody, can improve bone quality in women with Osteogenesis imperfecta. After 12 months, spinal areal bone mineral density increased, showing a beneficial treatment effect, although changes in hip bone density and bone structure were less pronounced than in women with severe osteoporosis.PurposeOsteogenesis imperfecta (OI) is the most common hereditary bone disorder, characterized by increased bone fragility and impaired bone quality, but pharmacological treatment is limited. Ongoing clinical trials investigate monoclonal anti-sclerostin antibodies for OI patients, offering new hope for reducing bone fragility by increasing bone mass.MethodsPostmenopausal women with either OI (n = 5) or severe osteoporosis (OPO, n = 10) receiving Romosozumab monthly (210 mg s.c.) for 12 months were analyzed retrospectively. Clinical assessments were performed at baseline, after 6 months, and after 12 months. Bone mass and structure were evaluated at baseline and after 12 months of treatment. In addition, serum and urine markers of bone turnover were analyzed at each time point.ResultsThe mean age of the participants was 53.6 ± 8.9 years for OI patients and 57.2 ± 5.8 years for OPO patients (p = 0.444). After 12 months of Romosozumab treatment, spinal aBMD and osteocalcin increased significantly in OI patients, indicating an anabolic response. HR-pQCT analysis revealed no statistically significant microstructural changes in patients with OI, although trends and moderate effect sizes suggested potential improvements. In patients with OPO, we observed a more pronounced response of bone turnover markers with greater aBMD gains at both the spine and femur, as well as significant improvements in bone microstructure, particularly at the tibia.ConclusionsRomosozumab treatment in postmenopausal women with OI resulted in a significant increase in spinal aBMD, though the effect on hip aBMD and peripheral bone microstructure was limited in contrast to postmenopausal osteoporosis.