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

Hu, J.; Zhou, B.; Lin, X.; Zhang, Q.; Guan, F.; Lei, S.; Liu, J.; Wang, O.; Jiang, Y.; Xia, W.-b.; Xing, X.; Li, M.

doi:10.1101/2022.06.29.498081

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bioRxiv · 10.1101/2022.06.29.498081

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

Hu, J.·Zhou, B.·Lin, X.·Zhang, Q.·Guan, F.·Lei, S.·Liu, J.·Wang, O.·Jiang, Y.·Xia, W.-b.·Xing, X.·Li, M.

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Abstract

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 (PLS3E10-16del/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 PLS3E10-16del/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.

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Hu, J., Zhou, B., Lin, X., Zhang, Q., Guan, F., Lei, S., Liu, J., Wang, O., Jiang, Y., Xia, W.-b., Xing, X., Li, M.. 2022-07-02. Impaired bone strength and bone microstructure in a novel early-onset osteoporotic rat model with a clinically relevant PLS3 mutation. https://doi.org/10.1101/2022.06.29.498081

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