Mechanisms of TNF-α– and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis

Abstract

Psoriatic arthritis (PsA) is an inflammatory joint disease characterized by extensive bone resorption. The mechanisms underlying this matrix loss have not been elucidated. We report here that blood samples from PsA patients, particularly those with bone erosions visible on plain radiographs, exhibit a marked increase in osteoclast precursors (OCPs) compared with those from healthy controls. Moreover, PsA PBMCs readily formed osteoclasts in vitro without exogenous receptor activator of NF-κB ligand (RANKL) or MCSF. Both osteoprotegerin (OPG) and anti-TNF antibodies inhibited osteoclast formation. Additionally, cultured PsA PBMCs spontaneously secreted higher levels of TNF-α than did healthy controls. In vivo, OCP frequency declined substantially in PsA patients following treatment with anti-TNF agents. Immunohistochemical analysis of subchondral bone and synovium revealed RANK-positive perivascular mononuclear cells and osteoclasts in PsA specimens. RANKL expression was dramatically upregulated in the synovial lining layer, while OPG immunostaining was restricted to the endothelium. These results suggest a model for understanding the pathogenesis of aggressive bone erosions in PsA. OCPs arise from TNF-α–activated PBMCs that migrate to the inflamed synovium and subchondral bone, where they are exposed to unopposed RANKL and TNF-α. This leads to osteoclastogenesis at the erosion front and in subchondral bone, resulting in a bidirectional assault on psoriatic bone

IL-1 mediates TNF-induced osteoclastogenesis

“…Activated T lymphocytes and synovial cells, in states of skeletal inflammation, also express the osteoclastogenic molecule. On the other hand, TNF is probably the dominant cytokine extant in inflammatory osteolysis (4)(5)(6)(7)(8). While TNF-induced osteoclastogenesis requires at least constitutive levels of RANKL, a synergistic relationship exists between the 2 cytokines in directly inducing marrow macrophages to commit to the osteoclast phenotype (9).…”

M-CSF mediates TNF-induced inflammatory osteolysis

“…This molecule, which is produced in abundance in bone erosive diseases such as rheumatoid arthritis and periodontitis (5)(6)(7)(8)(9), profoundly accelerates the osteoclastogenic process (10). Interestingly, TNF-α alone is not sufficient to promote osteoclast precursor differentiation but has an impact only on cells simultaneously stimulated, or primed, with RANKL (10).…”

NF-κB–inducing kinase controls lymphocyte and osteoclast activities in inflammatory arthritis

“…Although the factors initiating this disease are not fully understood, its progression can be largely attributed to the activation of lymphocyte and osteoclast (OC) lineages (1). Other forms of inflammatory arthritis, such as that accompanying psoriasis, have similar pathogenesis (2,3).…”