Tumor necrosis factor alpha and interleukin-6 drive a RANK-independent pathway of osteoclast activation
Fissel, Brian Michael
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The skeleton is a dynamic organ that undergoes a continual process known as bone remodeling. Bone remodeling is necessary to maintain structural integrity, heal micro-fractures caused by from daily wear and tear, and to store and release essential ions and minerals. Remodeling is a highly regulated process, with bone resorption precisely balanced by bone formation under homeostatic conditions. In the setting of rheumatoid arthritis (RA), an inflammatory condition affecting joints, this balance is lost and bone around inflamed joints is eroded. These so-called "bone erosions" compromise joint function, causing disability. Osteoclasts, multinucleated cells of hematopoietic origin, are the only cells known to resorb bone. Osteoclasts are found at erosion sites in human joints, and data from mouse models of inflammatory arthritis suggest that osteoclasts are required for erosions to form in bone. The canonical pathway of osteoclast differentiation requires stimulation of myeloid precursors by the cytokine Receptor Activator of NF-Kappa B ligand (RANKL) through its receptor, RANK. In the inflamed joint, RANKL expression can be induced on mesenchymal lineage cells by inflammatory cytokines such as tumor necrosis factor alpha (TNF alpha). Surprisingly, our lab observed bone erosions and osteoclast formation in a mouse model of RA in the absence of RANK. Thus we hypothesized that in addition to RANKL expression, the cytokine milieu in RA may directly stimulate osteoclast formation. It was recently reported that the inflammatory cytokines TNF alpha and interleukin-6 (IL-6) in combination stimulate osteoclast differentiation, independent of exogenous RANKL. We have reproduced these results and shown that these osteoclast-like cells form entirely independently of RANK signaling. However, TNF alpha/IL-6 induced osteoclast formation still requires the transcription factor Nuclear Factor of Activated T cells (NFATc1), a master regulator of RANK-mediated osteoclast differentiation, as well as co-stimulatory signaling provided by the immunoreceptor tyrosine based activation motif (ITAM)-containing DNAX-activating protein (DAP12) molecules. We also showed that TNF alpha/IL-6 induced osteoclast formation requires activity of IL-6 receptor (IL-6R), as osteoclast formation can be inhibited through co-culture with an IL-6R blocking antibody (MR16-1). Finally, using an in vivo mouse model of RA in RANK-deficient mice, we tested whether blocking IL-6R with MR16-1 antibody protects against the formation of periarticular bone erosions. Our results suggest that a RANK-independent pathway of osteoclast formation contributes to inflammatory bone erosions. Targeting this pathway may improve outcomes for RA patients.