Impaired bone strength and bone microstructure in a novel early-onset osteoporotic rat model with a clinically relevant <i>PLS3</i> mutation.

Abstract

Plastin 3 (PLS3), a protein involved in formation of filamentous actin (F-actin) bundles, is important in human bone health. Recent studies identify <i>PLS3</i> as a novel bone regulator and <i>PLS3</i> mutations can lead to a rare monogenic early-onset osteoporosis. However, the mechanism of <i>PLS3</i> mutation leading to osteoporosis is unknown, and its effective treatment strategies have not been established. Here, we have constructed a novel rat model with clinically relevant hemizygous E10-16del mutation in <i>PLS3</i> (<i>PLS3^E10-16del/0</i>) that recapitulates the osteoporotic phenotypes with obviously thinner cortical thickness, significant decreases in yield load, maximum load, and breaking load of femora at 3, 6, 9 months old compared to wild-type rats. Histomorphometric analysis indicates a significantly lower mineral apposition rate in <i>PLS3^E10-16del/0</i> rats. Treatment with alendronate (1.0 µg/kg/day) or teriparatide (40 µg/kg five times weekly) for 8 weeks significantly improves bone mass and bone microarchitecture, and bone strength is significantly increased after teriparatide treatment (p＜0.05). Thus, our results indicate that <i>PLS3</i> plays an important role in the regulation of bone microstructure and bone strength, and we provide a novel animal model for the study of X-linked early-onset osteoporosis. Alendronate and teriparatide treatment could be a potential treatment for early-onset osteoporosis induced by <i>PLS3</i> mutation.