Bone Abstracts

Osteogenesis Imperfecta (OI) is characterized by low bone mass, reduced bone strength and fractures. About 90% of OI cases are caused by autosomal dominant mutations in type I collagen (COL1A1 and COL1A2). Recessive OI can be caused by mutations in members of the prolyl-3-hydroxylation complex, including cartilage associated protein (CRTAP), that is important for post-translational collagen modification. The phenotypic overlap between dominant and recessive OI suggests common pathomechanisms. Previously, in bones of mouse models of moderate/severe recessive (Crtap−/−) and dominant OI (G610C OI; glycine substitution in Col1a2), we found an increased signaling of transforming growth factor beta (TGF-β), an important regulator of bone remodeling and bone mass. Interestingly, treatment with the TGF-β-neutralizing antibody 1D11 increased the trabecular bone volume/total volume (BV/TV) in the spine to WT levels in female mice of both models. Moreover, 1D11 increased whole bone strength of femurs of Crtap−/− mice, but did not improve the increased brittleness of the bone material. Together, these findings indicate that dysregulated TGF-β signaling is a common molecular mechanism contributing to the bone defects in these models of recessive and dominant OI. Recently, Tauer and colleagues reported increased TGF-β signaling also in bones of a different model of severe dominant OI with a high incidence of spontaneous fractures (Col1a1Jrt/+ mice with a Col1a1 splice site mutation, leading to an 18 amino acid deletion in Col1a1). In male Col1a1Jrt/+ mice TGF-β inhibition with 1D11 was less effective and lead to only minor trends to higher BV/TV in vertebrae and femurs that were not statistically significant. In summary, these findings demonstrate increased TGF-β signaling in different mouse models of OI; however, the efficacy of pharmacological TGF-β inhibition to improve bone mass may be modulated by the underlying genetic cause and/or severity of OI, as well as mouse gender or genetic background. In OI patients, the safety of TGF-β inhibition is currently tested in a phase 1 clinical trial using Fresolimumab, a human analog of 1D11. The exploratory endpoints may provide additional information regarding the role of OI genotype and severity on the effects of TGF-β inhibition on bone turnover and bone mass.

Disclosure: Anti-TGBβ antibody 1D11 was provided by Genzyme/Sanofi.

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