Bisphosphonates inhibit phosphorylation of signal transducer and activator of transcription 3 and expression of suppressor of cytokine signaling 3: implications for their effects on innate immune function and osteoclastogenesis

ObjectiveThis study tested the effects of bisphosphonates (BPs) on the suppressor of cytokine signaling 3 (SOCS3) protein in macrophages. SOCS3 has been shown to regulate cell differentiation and survival; however, its potential role in mediating the effects of BPs has not been explored.Study designThe cell viability of murine RAW 267.4 macrophages was assessed after culturing with control medium or media containing increasing concentrations of 2 BPs (ibandronate or clodronate) for 24, 48, and 72 hours. The phosphorylation status of signal transducer and activator of transcription 3 (STAT3) and the expression of SOCS3 protein levels were determined by Western blot analysis.ResultsIn control cultures, STAT3 phosphorylation and STAT3 and SOCS3 protein levels increased within 5 minutes after the addition of fresh medium. This increase was inhibited in cultures treated with both BPs. Macrophage cell viability also decreased after BP treatment.ConclusionsThese data demonstrate that, in addition to their effects on macrophage viability, BPs can decrease STAT3 and SOCS3 expression, which are important modulators of immune responses and bone homeostasis.