Mycobacterium tuberculosis specific protein Rv1509 modulates osteoblast and osteoclast differentiation via TLR2 signaling

Tuberculosis (TB), caused by <i>Mycobacterium tuberculosis</i> (<i>M.tb</i>), is one of the most ancient diseases recorded. In cases of bone TB, it significantly disrupts bone homeostasis, though the precise mechanisms are poorly understood and effective treatment targets are scarce. Our study investigated the role of Rv1509 in the pathogenesis of bone TB. We found that Rv1509 enhances the differentiation of bone marrow macrophages (BMMs) into osteoclasts by activating the TLR2 pathway, which stimulates the production of IL-6 and TNF-α. This, in turn, indirectly inhibits osteoblast differentiation and mineralization. Additionally, Rv1509 directly impairs osteoblast function and enhances the secretion of RANKL via TLR2 signaling, creating a detrimental RANKL/OPG imbalance that promotes osteoclast differentiation and bone degradation. Notably, the injection of Rv1509 into mouse skulls led to extensive bone damage, highlighting its significant role as a virulence factor in the pathogenesis of bone TB.