Synergy between IL-6 and soluble IL-6 receptor enhances bone morphogenetic protein-2/absorbable collagen sponge-induced bone regeneration via regulation of BMPRIA distribution and degradation

Bone morphogenetic protein-2/absorbable collagen sponge (BMP-2/ACS) implants have been approved for clinical use to induce bone regeneration. We previously showed that exaggerated inflammation characterized by elevated level of inflammatory cytokines including TNF-α, IL-1β, and IL-6 has been shown to inhibit BMP-2/ACS-induced bone regeneration. Furthermore, unlike the negative effects of TNF-α and IL-1β, IL-6 seemed not to affect BMP-2-induced osteoblastic differentiation of bone marrow mesenchymal stem cells (BMSCs). We hypothesized that there may be a regulatory loop between IL-6 and BMP-2 singling to affect BMP-2/ACS-induced bone regeneration. Here, we established a BMP-2/ACS-induced ectopic bone formation model in rats and fund that IL-6 injection significantly increased BMP-2/ACS-induced bone mass. Consistent with this animal model, an in vitro study demonstrated that synergy between IL-6 and soluble IL-6 receptor (IL-6/sIL-6R) promotes BMP-2-induced osteoblastic differentiation of human BMSCs through amplification of BMP/Smad signaling. Strikingly, IL-6 injection did not activate osteoclast-mediated bone resorption in the ectopic bone formation model, and IL-6/sIL-6R treatment did not affect receptor activator of NF-κB ligand (RANKL)-induced osteoclastic differentiation of human peripheral blood mononuclear cells (PBMCs) in vitro. Furthermore, IL-6/sIL-6R treatment did not affect expression of BMP receptors, but enhanced the cell surface translocation of BMP receptor IA (BMPRIA) and inhibited the degradation of BMPRIA. Collectively, these findings indicate that synergy between IL-6 and sIL-6R promotes the cell surface translocation of BMPRIA and maintains the stability of BMPRIA expression, leading to enhanced BMP-2/ACS-induced bone regeneration.