Minocycline to be used a potential anti-bone resorption agents due to the suppression of osteoclastic bone resorption

Tetracyclines such as doxycycline and minocycline are used to suppress bacterial growth in patients with inflammatory diseases. Tetracyclines have been shown to prevent bone loss, but the underlying mechanisms are unknown. Osteoclasts and dendritic cells (DCs) are derived from common progenitors such as bone marrow-derived macrophages (BMMs). Here, we showed that minocycline converts the differentiation pathway, which results in DC-like cells and not osteoclasts. Minocycline inhibited the receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis of BMMs but had no effects on cell growth and phagocytic activity. It influenced neither the proliferation nor differentiation of bone-forming osteoblasts. Surprisingly, minocycline induced the expression of DC markers, CD11c and CD86, in BMMs in the presence of RANKL. STAT5 is involved in DC differentiation that is induced by granulocyte-macrophage colony-stimulating factor (GM-CSF). Midostaurin, which is a STAT5 signaling inhibitor and an anti-GM-CSF neutralizing antibody, suppressed the differentiation that was induced by GM-CSF but not by tetracyclines. In vivo, the injection of minocycline into RANKL-injected mice and RANKL-transgenic mice suppressed RANKL-induced osteoclastogenesis and promoted the concomitant appearance of CD11c-positive cells. These results suggest that minocycline prevents bone loss that is induced by local inflammation, including rheumatoid arthritis and periodontitis, through osteoclast-DC-like cell conversion.