The role of PLS3 in the pathogenesis of osteoporosis

Abstract

Osteoporosis is a worldwide healthcare problem associated with significant mortality and morbidity. Studies of monogenic disorders that cause extreme skeletal phenotypes have led to the discovery of many genes involved in the regulation of bone turnover. Inactivating mutations in PLS3 cause juvenile onset X-linked osteoporosis, whilst PLS3 polymorphisms have also been associated with BMD in population studies of postmenopausal women. PLS3 encodes the actin-binding protein Plastin-3 and is expressed widely but its physiological function remains poorly understood. I hypothesise that Plastin-3 is essential for normal bone structure and strength and that Pls3-knockout (KO) mice provide a suitable disease model in which to investigate the underlying pathogenesis. I determined the developmental and adult skeletal phenotypes of Pls3 knockout mice (n≥6 per sex, age, and genotype). Although prenatal and postnatal skeletal development were normal, X-ray microradiography demonstrated that bone mineral content was reduced in femurs and lumbar vertebrae of Pls3-KO male mice compared to wild-type at postnatal day 70 (P70) and P183. Furthermore, micro-CT showed that femur cortical thickness was reduced at P70 and P183, and trabecular bone volume was decreased at P183. 3-point bend testing was performed to determine the consequences of this osteoporotic phenotype on bone strength. Load strength was reduced in P70 and P183 femurs. Though caudal vertebrae were normal, lumbar vertebral bone volume was decreased at P183 and biomechanical testing demonstrated reduced bone strength. Study of bone formation and bone resorption and bone turnover markers was normal overall, despite a few individual significant results. Taken together, these results showed an osteoporotic phenotype that is progressive with age, but the cellular basis for the phenotype remains uncharacterised. Pls3-KO mice recapitulate and extend the human phenotype observed in families with PLS3 mutations, and thus represent a tractable model to determine the mechanisms of disease and identify novel therapeutic targets.