Bone destruction is a common feature of inflammatory arthritis and is mediated 
by osteoclasts, the only specialized cells to carry out bone resorption. 
Aberrant expression of receptor activator of nuclear factor kappa β ligand 
(RANKL), an inducer of osteoclast differentiation has been linked with bone 
pathology and the synovial fibroblast in rheumatoid arthritis (RA). In this 
manuscript, we challenge the current concept that an increase in RANKL 
expression governs osteoclastogenesis and bone destruction in autoimmune 
arthritis. We isolated human fibroblasts from RA, pyrophosphate arthropathy 
(PPA) and osteoarthritis (OA) patients and analyzed their RANKL/OPG expression 
profile and the capacity of their secreted factors to induce osteoclastogenesis. 
We determined a 10-fold increase of RANKL mRNA and protein in fibroblasts 
isolated from RA relative to PPA and OA patients. Peripheral blood mononuclear 
cells (PBMC) from healthy volunteers were cultured in the presence of RA, PPA 
and OA synovial fibroblast conditioned medium. Osteoclast differentiation was 
assessed by expression of tartrate-resistant acid phosphatase (TRAP), 
vitronectin receptor (VNR), F-actin ring formation and bone resorption assays. 
The formation of TRAP(+), VNR(+) multinucleated cells, capable of F-actin ring 
formation and lacunar resorption in synovial fibroblast conditioned medium 
cultures occured in the presence of osteoprotegerin (OPG) a RANKL antagonist. 
Osteoclasts did not form in these cultures in the absence of macrophage colony 
stimulating factor (M-CSF). Our data suggest that the conditioned medium of pure 
synovial fibroblast cultures contain inflammatory mediators that can induce 
osteoclast formation in human PBMC independently of RANKL. Moreover inhibition 
of the TNF or IL-6 pathway was not sufficient to abolish osteoclastogenic 
signals derived from arthritic synovial fibroblasts. Collectively, our data 
clearly show that alternate osteoclastogenic pathways exist in inflammatory 
arthritis and place the synovial fibroblast as a key regulatory cell in bone and 
joint destruction, which is a hallmark of autoimmune arthritis.