Anti-TGF-β treatment shows increased bone mass and strength in a novel mouse model for osteogenesis imperfecta type I

Anti-Transforming growth factor beta (TGF-β) is a promising approach for the treatment of osteogenesis imperfecta (OI). To date, preclinical and clinical studies for the use of anti-TGF-β therapy have focused on moderate to severe OI caused by qualitative defects in collagen. However, the majority of OI patients are represented by type I OI. Haploinsufficiency of type I collagen causes OI type I. To study the effect of anti-TGF-β therapy in type I OI, we generated novel mouse model for OI type I. CMV-CRE mice were crossed to mice where Col1a1 was floxed between exon 2 and 5 to create a full body heterozygous deletion of Col1a1. Haploinsufficiency in the tibia was confirmed by decreased Col1a1 mRNA and protein expression. Comparable to OI patients, we observed reduced bone mass by μCT in these Col1a1+/- mice. Biomechanical measurements showed a decrease in bone strength and an increase in bone brittleness. Histomorphometric analysis showed an increase in osteoclast number and a trend towards increased osteoblasts. Overall suggesting this mouse shows a phenotype overlapping with OI type I. Upon treatment with a pan anti-TGF-β antibody, 1D11, this mouse model of OI type I showed increased bone mass. anti-TGF-β treatment further improved ultimate strength in the Col1a1+/- mice, but measures of ductility did not show improvement. Overall, our findings support expanding research on anti-TGFβ treatment for OI to OI caused by haploinsufficiency for type I collagen. tibias from 12 week old female Col1a1+/- and WT mice were used for RNA isolation. 3 samples for each group. Library prep was performed by poly-A selection