RANKL-independent modulation of osteoclastogenesis.

Osteoclasts are functional cells required for bone resorption. They are derived from hematopoietic precursors and undergo a series of differentiation and fusion steps in response to various humoral factors. Depending on the importance in osteoclastogenesis, the pathways for the differentiation of hematopoietic precursors to mature osteoclasts can be divided into two categories: canonical and the non-canonical. Receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast formation is considered as an important canonical pathway. Non-canonical pathways of osteoclastogenesis mainly involve several humoral factors that can substitute for RANKL to induce osteoclast formation. Among these factors, tumor necrosis factor (TNF)-α, interleukin (IL)-1, "homologous to lymphotoxins, exhibiting inducible expression, and competing with herpes simplex virus glycoprotein D for herpesvirus entry mediator, a receptor expressed by T lymphocytes" (LIGHT), a proliferation-inducing ligand (APRIL), and B cell-activating factor (BAFF) belong to the TNF superfamily. Other RANKL substitutes are primarily cytokines and growth factors including transforming growth factor β (TGFβ), IL-6, IL-11, nerve growth factor (NGF), insulin-like growth factor (IGF)-I, and IGF-II. In this review, we summarize the involvement of these factors in inducing osteoclastogenesis in vitro. Although these factors weakly induce osteoclast formation, they may play a major role in pathological bone resorption.