In this issue of JBMR, Tsukasaki and colleagues (1) challenged the concept of RANKL-independent osteoclastogenesis, which was recently reported in Nature.(2) This report will interest the readers of JBMR because of the long-standing debate regarding RANKL-independent osteoclastogenesis. Coordinated regulation of osteoclasts and osteoblasts is required for maintaining the skeletal homeostasis, and its imbalance is observed in various diseases such as rheumatoid arthritis (RA), postmenopausal osteoporosis, and tumor-induced bone diseases. RANKL (encoded by the Tnfsf11 gene), a member of the tumor necrosis factor (TNF) family, is an essential cytokine for osteoclast differentiation. RANKL binds to its receptor RANK (encode by the Tnfrsf11a gene) expressed by osteoclast precursor cells and activates various intracellular signaling cascades.(3, 4) The indispensable role of RANKL/RANK pathways was evidenced by genetic findings that mice with targeted disruption of either the Tnfsf11 or Tnfrsf11a gene exhibit severe osteopetrosis due to the complete absence of osteoclasts, and mutations in the TNFSF11 gene cause autosomal recessive osteopetrosis in humans.(5, 6) These findings clearly support the idea that the RANKL/RANK axis is indispensable for osteoclastogenesis in both physiological and pathological conditions. Nevertheless, the possibility of RANKL-independent osteoclastogenesis has fascinated researchers for long time, in particular under some disease conditions such as RA, and a number of studies supporting the presence of RANKL-independent osteoclastogenesis have been published: TNF-a,(7-9) APRIL, BAFF, NGF, IGF I, IGF II,(10) LIGHT,(11) TGF-b,(12) IL-6, IL-11,(13) and SOFAT (14) have been proposed as RANKL-independent osteoclastogenic factors.

TGF-b is a cytokine with ubiquitous proliferation and differentiation activity in many types of cells, and is abundantly stored in bone.(15) Although the role of TGF-b in bone milieu has been extensively studied, it is still controversial whether TGF-b promotes or inhibits osteoclastogenesis. It was reported that TGF-b directly acts on bone marrow macrophages and promotes osteoclastogenesis, whereas it inhibits osteoclastogenesis indirectly through the effect on bone marrow stromal cells or osteoblasts.(16-19) We recently reported that although the presence of TGF-b is indispensable for RANKL-induced osteoclastogenesis, TGF-b alone did not induce osteoclastogenesis.(20)