BoneKEy-Osteovision | Commentary
RANKL limits its own osteoclastogenic effect
DOI:10.1138/2002054
Commentary on: Takayanagi H, Kim S, Matsuo K, Suzuki H, Suzuki T, Sato K, Yokochi T, Oda H, Nakamura K, Ida N, Wagner EF, Taniguchi T. RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-beta. Nature. 2002 Apr 18;416(6882):744-9.
Those who work on the biology of bone should feel happy to know that our colleagues in immunology and hematology must now realize how important the skeleton is. No longer can they regard it as an inert packaging structure for their interesting cells and cytokines, now that so many of their favorite cytokines and control mechanisms have emerged with crucial roles in the maintenance of a normal skeletal mass. There is a long and increasing list of cytokines whose genetic ablation or overexpression results in severe bone phenotypes, either osteopetrosis or osteoporosis, resulting from inadequate or excessive osteoclast formation respectively. From the evolutionary point of view, it identifies the importance for survival of the tightly regulated processes of bone resorption and formation in bone remodeling, so that skeletal strength and form can be maintained.
An entirely novel and fascinating control mechanism comes to us now in the work of Takayanagi et al.(), who have identified IFN-β as a product of RANKL stimulation in monocytic osteoclast precursors, which inhibits osteoclast formation by preventing RANKL-induced expression of c-Fos. The latter is known to be an essential transcription factor in osteoclast differentiation, having provided one of the earliest osteopetrotic phenotypes following c-Fos ablation (). The IFN-β production was discovered in the course of a program seeking RANKL-induced genes, and the link with osteoclast formation established by showing that mice deficient in one of the IFN-αβ receptor components (IFNAR-/-mice) were osteoporotic, and their hemopoietic cells had increased osteoclast formation in response to RANKL. IFN-β inhibited osteoclast formation in vitro, a response that could be abrogated by adenovirally transfected c-Fos. Furthermore in a disease model, IFN-β treatment prevented the induction of bone loss that occurs with injection of lipopolysaccharide (LPS). The authors produce compelling evidence that IFN-β is a RANKL-induced inhibitor of RANKL action, potentially an important mechanism by which osteoclastogenesis is inhibited by the very factor that promotes it, thus identifying a new autocrine control mechanism. One might even speculate that this “self regulation” might be a key factor in determining the extent of resorption at remodeling sites in bone.
Previous recognized roles of IFN-α and IFN-β were in host defence against virus and other pathogens (). With a common receptor, they have signalling mechanisms that are similar but not identical. The work of Takayanagi et al. identifies a previously unknown signalling mechanism of IFN-β, in that it operates via c-Fos to maintain bone homeostasis. IFN-α was not induced by RANKL under conditions of IFN-β induction, and studies of the RANKL induction of IFN-β promoter indicated also that the response is specific to IFN-β, not α. The signaling mechanisms in the IFN-β response will be of considerable interest, but appear to involve the transcription factor complex, ISGF3. The suppressive effect of IFN-β on osteoclast formation in PKR-/-mice was partially attenuated, pointing to possible participation of double-stranded-RNA-activated protein kinase (PKR), which is induced by IFN-β activation of ISFG (). Other target genes would arise in this pathway.
The discovery of OPG, a soluble member of the TNF receptor family, as a powerful inhibitor of bone resorption (), provided the means of identifying and cloning RANKL - the common factor mediating osteoclast formation in response to all known stimuli (). The presence of such a membrane-associated molecule in cells of the osteoblast lineage had long been suspected, and these discoveries explained how osteoclast formation is controlled by the osteoblast lineage (). All of this was validated by studies in genetically altered mice, with overexpression of OPG resulting in mice with osteopetrosis because they failed to produce osteoclasts, and ablation of OPG leading to severe osteoporosis (). Similarly, genetic ablation of RANKL resulted in osteoporosis, and ablation of its receptor, RANK, to osteopetrosis ().
The link between osteoclastogenesis and the immune system is consolidated by these events of the last few years. At about the same time that OPG, RANKL and RANK were discovered as bone-active agents, RANKL was discovered as a product (TRANCE) of the T-cells, related to the mechanism by which those cells present antigen by interacting with RANK on dendritic cells. Other links with the immune system have been accumulating. Activated T cells promote periarticular bone loss in experimental arthritis through production of soluble RANKL (). Enhanced production of TNF-α by T cells is invoked as a mechanism contributing to bone loss in osteoporosis (), IL-7 induces release of soluble osteoclastogenic cytokines from T cells (), and the T-cell cytokine IL-17, promotes osteoclast formation and bone resorption (). The cells of the immune system harbour potent inhibitors of osteoclast formation also. IFN-γ is a potent T-cell derived inhibitor of osteoclast formation, and the stromal cell-derived IL-18 does so by acting upon the T-cell to promote GM-CSF release (). It also synergizes with IL-12 to generate an as yet uncharacterized inhibitor of osteoclast formation from T cells ().
It almost seems as though osteoclast formation is too simple and straightforward with promotion by RANKL. But the process needs to be tightly regulated during bone remodeling in order to achieve and maintain skeletal strength and form. At sites of resorption, osteoclasts need to be formed, and they exert their activity over a period of several days before the reversal phase of remodeling begins. If RANKL-induced osteoclast formation were to go unchecked, resorption would inevitably be excessive. We have always had the question before us - why does a certain amount of resorption take place in a Howship's lacuna, and only that much? Research has concentrated on local stimulators of osteoclast formation and activity, with only OPG emerging as a potential paracrine mechanism of inhibition of osteoclast formation during remodeling. The T-cell inhibitors have always seemed more likely to make their contribution under pathological conditions, especially in inflammatory bone disease. Although OPG remains as a candidate contributor, RANKL-induced IFN-β provides an appealing mechanism of control of osteoclast formation at critical sites in normal bone remodeling, a mechanism which is contained within the osteoclast lineage itself.
What is being built up is a concept of the prime importance of inhibitors of osteoclast formation. Maybe there can never be too many, given the relative simplicity and capacity of the osteoclastogenesis process, and the survival importance of maintaining skeletal structure and integrity.
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