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. 2002 Nov;61(Suppl 2):ii32–ii39. doi: 10.1136/ard.61.suppl_2.ii32

Role of RANKL and RANK in bone loss and arthritis

D Jones, Y Kong, J Penninger
PMCID: PMC1766717  PMID: 12379618

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Figure 1 .

Figure 1

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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 .

Figure 2

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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 .

Figure 3

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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.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

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