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.
Christopher T. Ritchlin, Sally A. Haas-Smith, Ping Li, David G. Hicks, Edward M. Schwarz
β3 integrin–null osteoclasts are dysfunctional, but their numbers are increased in vivo. In vitro, however, the number of β3–/– osteoclasts is reduced because of arrested differentiation. This paradox suggests cytokine regulation of β3–/– osteoclastogenesis differs in vitro and in vivo. In vitro, additional MCSF, but not receptor activator of NF-κB ligand (RANKL), completely rescues β3–/– osteoclastogenesis. Similarly, activation of extracellular signal-regulated kinases (ERKs) and expression of c-Fos, both essential for osteoclastogenesis, are attenuated in β3–/– preosteoclasts, but completely restored by additional MCSF. In fact, circulating and bone marrow cell membrane-bound MCSFs are enhanced in β3–/– mice, correlating with the increase in the osteoclast number. To identify components of the MCSF receptor that is critical for osteoclastogenesis in β3–/– cells, we retrovirally transduced authentic osteoclast precursors with chimeric c-Fms constructs containing various cytoplasmic domain mutations. Normalization of osteoclastogenesis and ERK activation, in β3–/– cells, uniquely requires c-Fms tyrosine 697. Finally, like high-dose MCSF, overexpression of c-Fos normalizes the number of β3–/– osteoclasts in vitro, but not their ability to resorb dentin. Thus, while c-Fms and αvβ3 collaborate in the osteoclastogenic process via shared activation of the ERK/c-Fos signaling pathway, the integrin is essential for matrix degradation.
Roberta Faccio, Sunao Takeshita, Alberta Zallone, F. Patrick Ross, Steven L. Teitelbaum
M. Neale Weitzmann, Cristiana Roggia, Gianluca Toraldo, Louise Weitzmann, Roberto Pacifici
Frank Rauch, Rose Travers, Horacio Plotkin, Francis H. Glorieux