NF-κB is a critical signal for osteoclast (OC) differentiation downstream of RANKL, and its disruption blocks bone loss in a variety of disease models in mice. Differently from other TNF family members, RANKL activates both the classical NF-κB pathway, activating p65 and cRel, and the alternative pathway, inducing expression and activation of RelB. Our studies on the role of individual NF-κB subunits have demonstrated that p65 is important for OC precursor survival during a critical period of differentiation but is not necessary for transcription of the OC differentiation program . In contrast, RelB is required for OC differentiation in vitro and for pathological bone loss in vivo . Both deletion and activation of NIK, the upstream kinase regulating RelB activation, significantly modulates osteoclastogenesis, especially in models of inflammatory arthritis. Thus, the alternative NF-κB pathway represents an interesting potential target for the control of bone loss in diseases such as rheumatoid arthritis.
Osteoclast Lineage RANKL Stimulation Serum TRAP5b Pathological Bone Loss Serum Transfer Arthritis
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