Pathological role of osteoclast costimulation in arthritis-induced bone loss

Osteoclasts, multinucleated cells of hematopoietic origin that degrade the bone matrix, are regulated by immunoregulatory molecules under both physiological and pathological conditions. Combined deficiency of Fc receptor common γsubunit (FcRγ) and DNAX-activation protein 12 (DAP12) results in a complete lack of osteoclasts. In addition to RANK, the receptor for RANK ligand (RANKL), the Ig-like receptors associated with FcRγ and DAP12 have been recognized as essential receptors for osteoclastogenesis. This observation established that Ig-like receptors function as osteoclast costimulatory receptors, which are crucial for bone homeostasis under physiological conditions.

Abnormal T cell immune responses induce aberrant expression of inflammatory cytokines such as TNF-α, leading to osteoclast-mediated bone erosion and osteoporosis in autoimmune arthritis. However, the mechanism underlying enhanced osteoclastogenesis in arthritis is not completely understood. A recent study [1] showed that TNF-α contributes to inflammatory bone loss by enhancing the osteoclastogenic potential of osteoclast precursor cells through inducing paired Ig-like receptor-A (PIR-A), a costimulatory receptor for RANK. In fact, bone erosion and osteoporosis, but not inflammation, caused by aberrant TNF-α expression were improved in mice deficient in Fc receptor common γ subunit or β2-microglobulin, in which the expression of PIR-As and PIR-A ligands is impaired, respectively.

These results establish the pathological role of costimulatory receptors for RANK in bone loss in arthritis and may provide a molecular basis for the future therapy of inflammatory diseases.

1. Ochi S et al. Proc Natl Acad Sci U S A. 2007;104: 11394-11399