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Non-canonical pathways of osteoclastogenesis have been described in which several cytokines are able to substitute for RANKL. These cytokines are few in number and their role(s) in pathological bone resorption has not been ascertained. We have identified five additional cytokines, APRIL, BAFF, NGF, IGF I and IGF II, that can induce RANKL-independent osteoclastogenesis. All five cytokines induced both osteoclast differentiation and activation with respect to the formation of significant numbers of TRAP(+) and VNR(+) multinucleated cells that were capable of resorbing bone. The number of TRAP(+) multinucleated cells that formed was in the range of 40-75% of that supported by MCSF plus RANKL. Resorption was at a similar level to that induced by the other known RANKL substitutes TNFα, IL-6 and TGF-β. The addition of osteoprotegrin, the endogenous decoy receptor of RANKL, revealed that this resorption was independent of RANKL. APRIL, BAFF, IGF I and IGF II were found to be expressed in giant cell tumour of bone. IGF I and IGF II demonstrated very strong expression in the stromal cell population of all tumour samples. This data suggests that non-canonical osteoclastogenesis plays a role in both normal and pathological bone resorption.

Original publication




Journal article



Publication Date





938 - 944


B-Cell Activating Factor, Humans, Insulin-Like Growth Factor I, Insulin-Like Growth Factor II, Nerve Growth Factor, Osteoclasts, RANK Ligand, Tumor Necrosis Factor Ligand Superfamily Member 13