Role of RANKL and RANK in bone loss and arthritis

Abstract

The tumour necrosis factor family molecule RANKL (RANKL, TRANCE, ODF) and its receptor RANK are key regulators of bone remodelling and regulate T cell/dendritic cell communications, and lymph node formation. Moreover, RANKL and RANK are expressed in mammary gland epithelial cells and control the development of a lactating mammary gland during pregnancy and the propagation of mammalian species. Importantly, RANKL and RANK are essential for the development and activation of osteoclasts and bone loss in response to virtually all triggers tested. Therapeutically, inhibition of RANKL function via the decoy receptor osteoprotegerin completely prevents bone loss at inflammed joints and has partially beneficial effects on cartilage destruction in all arthritis models studied. Modulation of these systems provides a unique opportunity to design novel treatments to inhibit bone loss and crippling in arthritis.

Figure 1

Regulation of osteoclast formation. Calciotropic factors such as vitamin D3, prostaglandin E₂, IL1, IL11, TNFα and glucocorticoid induce RANKL expression on osteoblasts. RANKL binding to the RANK expressed on haematopoietic progenitors activates a signal transduction cascade that leads to osteoclast differentiation in the presence of the survival factor CSF1. Moreover RANKL stimulates bone resorbing activity in mature osteoclasts via RANK. OPG produced by osteoblasts acts as a decoy receptor for RANKL and inhibits osteoclastogenesis and osteoclast activation by binding to RANKL. TGFß released from bone during active bone resorption has been suggested as one feedback mechanism for upregulating OPG. Oestrogen can increase OPG production on osteoblasts, which is a possible explanation of postmenopausal osteoporosis after oestrogen withdrawal.

Figure 2

RANK signalling. After RANKL biding, the TNFR member RANK sends signals into the cells through tumour necrosis factor receptor associated factors (TRAFs) 1, 2, 3, 5, and 6. c-Src and Cbl proteins associate with the cytoplasmatic tail of RANK. These RANK associated molecules relay RANK dependent stimulation to downstream pathways such as NF-kB, JNK/SAPK, p38, and Akt/PKB that regulate bone resorption, activation, survival, and differentiation of osteoclasts and dendritic cells. Interferon gamma can inhibit RANKL mediated osteoclastogenesis presumably via induction of TRAF6 ubiquitination and proteolytic TRAF6 degradation. The scheme is based on Arron and Choi.⁹²

Figure 3

Rational drug design to interfere with arthritic disease. Activated T cells produce cytokines such as TNFα, IL1, IL11, and IL17 that lead to RANKL expression on osteoblasts. Moreover, activated T cells directly express and produce RANKL that induces osteoclast formation and activation. The soluble decoy receptor for RANKL, OPG, blocks both pathways. In addition to inhibiting the functions of cytokines to alleviate inflammation, inhibition of RANKL via OPG might be useful to block osteoclast activation and crippling in arthritis irrespective of the disease trigger.