The Mechanism of Coupling between Bone Resorption and Formation

Deficiency of osteoprotegerin (OPG), a soluble decoy receptor for receptor activator of NF-κB ligand (RANKL), in mice induces osteoporosis caused by enhanced bone resorption but also accelerates bone formation. We examined if bone formation is coupled with bone resorption in OPG-deficient (OPG−/−) mice, using risedronate, an inhibitor of bone resorption. Histomorphometric analysis showed that bone formation-related parameters in OPG−/−mice sharply decreased with the suppression of bone resorption by the daily injection of risedronate for 30 days. OPG−/−mice exhibited high serum alkaline phosphatase activity and osteocalcin concentrations, both of which were decreased to the levels of wild-type mice by risedronate injection. The ectopic bone formation induced by bone morphogenetic protein-2 implantation into OPG−/−mice was not accelerated. These results suggest that bone formation is coupled with bone resorption at local sites in OPG−/−mice. Myeloid differentiation factor 88 (MyD88) plays essential roles in the signaling of the Toll/interleukin-1 (IL-1) receptor family. Toll-IL-1 receptor domain-containing adapter inducing interferon-β (TRIF)-mediated signals are involved in lipopolysaccharide (LPS)-induced MyD88-independent pathways. Using MyD88-deficient (MyD88−/−) mice and TRIF-deficient (TRIF−/−) mice, we examined the roles of MyD88 and TRIF in osteoclast differentiation and function. LPS and IL-1α stimulated osteoclastogenesis in co-cultures of osteoblasts and hemopoietic cells obtained from TRIF−/−mice but not MyD88−/−mice. Bone histomorphometry showed that MyD88−/−mice exhibited osteopenia with reduced bone resorption and formation. These results suggest that the MyD88-mediated signal is essential for the osteoclastogenesis and function induced by IL-1 and LPS, and that MyD88 is physiologically involved in bone turnover.