Bone Abstracts

Objectives: Osteogenesis Imperfecta (OI) is a collagen-related disorder. Type V OI, caused by a recurrent dominant mutation in the plasma membrane protein IFITM5/BRIL, and type VI OI, caused by recessive null mutations in the anti-angiogenic factor PEDF, have distinct features. IFITM5 S40L, reported in six patients, causes severe dominant OI with phenotype and bone histology similar to type VI, rather than Type V, OI. Our objective is to understand the pathway connecting IFITM5 and PEDF and its role in bone development.

Methods: We generated a conditional knock-in mouse model to investigate atypical type VI OI. The mutation, located at murine BRIL S42L, was activated using E2A-CRE mating. Heterozygous and homozygous mutant mice were analyzed at 1 and 2 months of age.

Results: BRIL S42L is non-lethal in both heterozygous and homozygous mice. Newborn heterozygous and homozygous S42L pups have flared rib cage, shoulder and knee dislocations, plus homozygotes have rib fractures and unmineralized calvaria. In radiographs, S42L heterozygous mice exhibit 60% humeral fractures in 1- (19/30 HETS) and 2-month-old (18/28 HETS) mice, while homozygotes incur fractures in 96% (30/31 HOMZ) of humerii, as well as femora and pelvis. Serum alkaline phosphatase was increased in 1-month-old heterozygous males (P<0.01) wrt WT, as occurs in typical and atypical OI type VI. Femora of 2-month old heterozygous males showed elevated TbN (P<0.05) on uCT, reduced stiffness, yield and ultimate load, with marked increase in brittleness. Biomechanics are not explained by change in bone size, suggesting material differences. Pore volume/BV was increased on uCT, consistent with increased vascularity. Whole body DXA aBMD was significantly decreased in 1 and 2 month-old heterozygotes (P<0.01) and 1-month-old S42L homozygotes. qBEI revealed increased mineralization in cancellous and cortical bone of 2 month-old heterozygous males. This is consistent with in vitro osteoblast studies from heterozygous mice which yielded increased mineralization by alizarin red staining (P<0.05) and increased expression levels of osteoblast genes throughout differentiation.

Conclusion: Taken together, the altered bone fragility, mineralization, vascularity and serum ALP indicate that the IFITM5 S42L mouse is an appropriate model to investigate the cellular and bone tissue mechanisms of atypical type VI OI.

Disclosure: The authors declared no competing interests.