Abstract
In the current study, we investigated how skeletal stem cells (SSCs) modulate inflammatory osteoclast (OC) formation and bone resorption. Notably, we found that intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and osteoprotegerin (OPG) play a synergistic role in SSC-mediated suppression of inflammatory osteoclastogenesis. The effect of SSCs on inflammatory osteoclastogenesis was investigated using a lipopolysaccharide-induced mouse osteolysis model in vivo and human osteoarthritis synovial fluid (OASF) in vitro. OC formation was determined by tartrate-resistant acid phosphatase staining. Bone resorption was evaluated by microcomputerized tomography, serum C-terminal telopeptide assay, and pit formation assay. The expression of ICAM-1, VCAM-1, and OPG in SSCs and their contribution to the suppression of osteoclastogenesis were determined by flow cytometry or enzyme linked immunosorbent assay. Gene modification, neutralization antibodies, and tumor necrosis factor-α knockout mice were used to further explore the mechanism. The results demonstrated that SSCs remarkably inhibited inflammatory osteoclastogenesis in vivo and in vitro. Mechanistically, inflammatory OASF stimulated ICAM-1 and VCAM-1 expression as well as OPG secretion by SSCs. In addition, ICAM-1 and VCAM-1 recruited CD11b+ OC progenitors to proximity with SSCs, which strengthened the inhibitory effects of SSC-derived OPG on osteoclastogenesis. Furthermore, it was revealed that tumor necrosis factor α is closely involved in the suppressive effects. In summary, SSCs express a higher level of ICAM-1 and VCAM-1 and produce more OPG in inflammatory microenvironments, which are sufficient to inhibit osteoclastogenesis in a "capture and educate" manner. These results may represent a synergistic mechanism to prevent bone erosion during joint inflammation by SSCs.