Ostm1 Bifunctional Roles in Osteoclast Maturation: Insights From a Mouse Model Mimicking a Human OSTM1 Mutation.

Ostm1 mutations are responsible for the most severe form of osteopetrosis in human and mice. To gain insight into Ostm1 cellular functions, we engineered a conditional in-frame deletion of the Ostm1 transmembrane domain and generated the first Ostm1 mouse model with a human mutation. Systemic targeting of Ostm1 loss of transmembrane domain produced osteopetrosis, as in the null Ostm1 gl/gl mouse. Significantly, conditional osteoclast targeting of Ostm1 resulted in similar osteopetrosis, thereby demonstrating that the intrinsic Ostm1 osteoclast deficiency is solely responsible for the mouse phenotype. Our analysis showed oversized osteoclasts with enhanced multinucleation associated with stimulation of intracellular calcium levels, of Nfatc1 nuclear re-localization, and of specific downstream Nfatc1 target genes, providing compelling evidence that Ostm1 is a negative regulator of preosteoclast fusion. Moreover, mature OCs with Ostm1 loss of transmembrane domain show appropriate levels of intracellular acidification but an altered distribution pattern, highlighting misregulation of endolysosome localization and dispersion. Consistently, the hydrolases tartrate-resistant acid phosphatase (TRAP) and cathepsin K (Ctsk) normally produced are sequestered within the osteoclasts and are not extracellularly secreted. These studies defined bifunctional roles for Ostm1 as a major regulator of preosteoclast cytoskeletal rearrangements toward cell multinucleation and of mature osteoclast intracellular lysosomal trafficking and exocytosis mechanism, both of which are essential for bone resorption. Importantly, these Ostm1 molecular and regulatory functions could serve as preclinical targets in this mouse model toward osteoclastogenic pathologies as osteoporosis and inflammation-induced bone loss. © 2018 American Society for Bone and Mineral Research.