Repurposing the multiple sclerosis drug Siponimod for osteoporosis treatment.

Osteoporosis is the most common bone disorder, in which an imbalance between osteoclastic bone resorption and osteoblastic bone formation disrupts bone homeostasis. Osteoporosis management using anti-osteoclastic agents is a promising strategy; however, this remains an unmet need. Sphingosine-1-phosphate (S1P) and its receptors (S1PRs) are essential for maintaining bone homeostasis. Here, we identified that Siponimod, a Food and Drug Administration-approved S1PR antagonist for the treatment of multiple sclerosis, shows promising therapeutic effects against osteoporosis by inhibiting osteoclast formation and function. We found that Siponimod inhibited osteoclast formation in a dose-dependent manner without causing cytotoxicity. Podosome belt staining and bone resorption assays indicated that Siponimod treatment impaired osteoclast function. Western blot and qPCR assays demonstrated that Siponimod suppressed the expression of osteoclast-specific markers, including C-Fos, Nftac1, and Ctsk. Mechanistically, we validated that Siponimod downregulated receptor activator of nuclear factor kappa B ligand (RANKL)-induced Mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB) signaling pathways during osteoclastogenesis. Moreover, in a preclinical mouse model, Siponimod prevented ovariectomy-induced bone loss by suppressing osteoclast activity in vivo. Collectively, these results suggest that Siponimod could serve as an alternative therapeutic agent for the treatment of osteoporosis.

Prevotella histicola Prevented Particle-Induced Osteolysis via Gut Microbiota-Dependent Modulation of Inflammation in Ti-Treated Mice.

Wear particles generated from total joint replacements induce chronic osteolysis mediated by inflammatory upregulation, which leads to implant failure. Recent studies have suggested an important role of the gut microbiota in modulating the host's metabolism and immune system, leading to alterations in bone mass. Following gavage with P. histicola, micro-CT and HE staining revealed that osteolysis was significantly reduced in titanium (Ti)-treated mice. Immunofluorescence analysis revealed an increased macrophage (M)1/M2 ratio in the guts of Ti-treated mice, which decreased when P. histicola was added. P. histicola was also found to upregulate the tight junction proteins ZO-1, occludin, claudin-1, and MUC2 in the gut, reduce the levels of inflammatory factors IL-1ß, IL-6, IL-8, and TNF-α, primarily in the ileum and colon, and decrease the expression of IL-1ß and TNF-α and increase the level of IL-10 in the serum and cranium. Furthermore, P. histicola treatment resulted in a significant downregulation of CTX-1, RANKL, and RANKL/OPG. These findings demonstrate that P. histicola significantly mitigates osteolysis in Ti-treated mice by improving intestinal microbiota that repairs intestinal leakage and reduces systemic and local inflammation which in turn inhibits RANKL expression for bone resorption. P. histicola treatment may thus be therapeutically beneficial for particle-induced osteolysis.