Impaired bone strength and bone microstructure in a novel early-onset osteoporotic rat model with a clinically relevant PLS3 mutation

Osteoporosis is a highly prevalent disorder with a strong genetic component. Recent studies identify PLS3 as a novel bone regulator of bone metabolism and PLS3 mutations lead to a rare monogenic early-onset osteoporosis. However, the mechanism of PLS3 mutation leading to osteoporosis is unknown with no animal models carrying patient-derived PLS3 mutations generated. The effective treatment strategies for PLS3-related have not been established. Here we have constructed a novel rat model with clinically relevant hemizygous E10-16del mutation of PLS3 (PLS3^E10-16del/0) that recapitulate 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 compared to WT rats. Histomorphometric analysis indicates a significantly lower mineral apposition rate in PLS3^E10-16del/0rats. Treatment with alendronate (ALN, 1.0 ug/kg per day) or teriparatide (TPTD, 40ug/kg five times weekly) for 8 weeks significantly improved bone mass and bone microarchitecture, and bone strength was significantly increased after TPTD treatment (P < 0.05). Thus, our results indicate the roles of PLS3 in the regulation of bone microstructure and bone strength, providing a novel animal model for the study of early-onset osteoporosis. Alendronate and teriparatide treatment could be a potential treatment for early-onset osteoporosis induced by PLS3 mutation.