Soluble RANKL in bone, immunity and cancer

Abstract

  Bone is a crucial element of the skeletal-locomotor system, but also functions as an immunological organ that harbors hematopoietic stem cells and immune progenitor cells. In addition, the skeletal and immune systems share variety of molecules, including cytokines and receptors. The term “osteoimmunology” was coined to describe the research on the shared molecules and interactions between the skeletal and immune systems, and has been developed mainly based on the studies on the pathogenesis of rheumatoid arthritis. The TNF family cytokine RANKL is one of the most typical “osteoimmune” factors. RANKL plays crucial roles in not only osteoclast differentiation, but also the immune organs including lymph nodes and thymus. Furthermore, excess RANKL signal causes abnormal osteoclast activation, resulting in a variety of skeletal diseases in patients with rheumatoid arthritis, osteoporosis and bone metastasis. A fully human anti-RANKL neutralizing antibody is now used in the treatment of bone loss disorders. RANKL is synthesized as a membrane-bound molecule, which is cleaved into soluble form by proteases. The functional difference between soluble and membrane-bound forms of RANKL has been poorly understood in vivo so far. Recently, we have elucidated the physiological and pathological significances of soluble RANKL by generating mice that selectively lack soluble RANKL. Here, I review the osteoimmunological function of RANKL and the distinct role of soluble RANKL in bone metastasis by introducing our recent research.