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Osteocytes are the major mechanosensors that respond to mechanical strain and regulate bone formation and resorption. Previous studies have indicated that IL-6 is a mechano-sensitive cytokine. However, there are few data describing the effect of IL-6 on osteoblasts and osteoclasts under mechanical loading. The purpose of this study was to evaluate whether osteocytes affect osteoblast differentiation and osteoclast activity via IL-6 production. Murine primary calvarial osteoblasts and RAW264.7 macrophage cells were cultured in conditioned medium collected from murine long bone osteocytes Y4 (MLO-Y4) subjected to compressive cyclic force (CCF) with or without IL-6 and soluble IL-6 receptor (sIL-6R). The results showed that MLO-Y4 osteocytes increased ALP activity and osteoblast markers expression in murine calvarial osteoblasts and inhibited osteoclastogenesis and osteoclast differentiation in osteoclast precursors via soluble factors in the CCF-induced conditioned medium (CCF CM). Typically, the osteocyte-induced effects were significantly greater in the presence of exogenous IL-6/sIL-6R. However, when the CCF CM was treated with the IL-6 neutralizing antibody, the stimulating effect was significantly blocked. Activation of Janus protein tyrosine kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase (ERK) signal transduction pathways were involved in IL-6-induced osteoblasts and osteoclast differentiation and activities. In conclusion, osteocytes regulate osteogenic response and osteoclast activity under mechanical loading through IL-6 production via the STAT3 and ERK signaling pathways. These pathways not only induce distinct biological responses, but also coordinate with each other to have detrimental effects on bone homeostasis.

Osteocytes regulate osteoblast differentiation and osteoclast activity through Interleukin-6 under mechanical loading