Where is rank ligand located

These data highlight the multiple levels of control that bone requires for proper homeostatic function, and suggest the potential that RANKL signaling has as a therapeutic target in treating bone-related ailments. In fact, denosumab, an anti-RANKL antibody is now in clinics for use in treating osteoporosis and shows promise for treating additional OC-related conditions Expansile skeletal hyperphosphatasia ESH is a genetic disorder characterized by early onset deafness, premature loss of teeth, progressive hyperostotic widening of long bones causing painful phalanges in the hands, accelerated bone remodeling, and episodic hypercalcemia.

While ESH is distinguished phenotypically from FEO by the presence of hypercalcemia and the absence of large osteolytic lesions with cortical thinning in major long bones, it appears also to occur from an activating mutation — in this case a bp tandem repeat — in the region encoding the RANK signal peptide Multiple additional mutations have been characterized in the gene encoding RANK that result in varied forms of osteopetrosis, but despite early onset, it has been shown in some cases that disease can be cured by hematopoietic stem cell transplant even when carried out in late infancy Genetic analysis determined that this disorder is the result of an inactivating mutation in the gene encoding OPG, and that serum levels of OPG are undetectable in affected individuals Cherubism is a rare autosomal dominant disease of the lower jaw characterized by excessive OC-mediated bone resorption and associated with mutations in the gene Sh3bp2 While the mechanism s disease onset was not initially understood, more recent work has demonstrated that the mutations appear to impact regions of scaffolding protein encoded by Sh3bp2 that coordinate signals converging from RANK and M-CSFR to activate Syk, PLCg2, and Vav These alterations in signaling complexes lead to increased TNF-a expression and augmented OC activity Much more common than bone pathologies caused directly by genetic lesions to the RANKL—RANK—OPG systems are bone-related pathologies that arise later due to environmental factors, homeostatic dysregulation, hormonal changes, or other disease sequelae.

The most common of these is post-menopausal osteoporosis, a skeletal disorder characterized by weakening of the bones and predisposition to fracture due to bone loss caused by an imbalance in OC activity versus new bone formation , Osteoporosis is associated with hormonal changes, such as decreased estrogen levels in post-menopausal women, and has been linked to increased RANKL levels on bone marrow cells of women exhibiting osteoporosis , Similarly, patients receiving hormone ablation therapy for breast cancer estrogen suppression or prostate cancer chemical or surgical castration for testosterone suppression may also suffer osteoporotic bone loss due to increased RANKL expression , In patients with bone metastases, skeletal complications caused by increased OC activity may result in pathological fractures, spinal cord compression, and the need for radiotherapy to the bone or orthopedic surgery [collectively known as skeletal-related events SREs ] Increased bone turnover may even enhance tumor growth in bone by facilitating the early establishment, as well as later progression, of bone metastases In the former case, some examples and mechanisms have been described.

For instance, bone pain and excessive OC activity are the primary complication for multiple myeloma patients, with increased levels of RANKL often found in bone stromal cells With respect to mechanisms of tumor-driven increases in RANK activity, one study showed tumor cell expression of metalloproteases ADAMTS1 and MMP1, factors associated with increased risk of metastasis in breast cancer, alter secretion of epidermal growth-like factors in a manner that suppresses OPG expression by resident OBs In another study, it was shown that prostate cancer cells expressing a soluble form of RANKL could directly induce osteoclastogenesis from precursor cells in the absence of stromal accessory cells With respect to promoting metastasis, interest in a potential role for RANKL—RANK was triggered by observations relating to its role in epithelial organogenesis, specifically mammary stem cell development, which could be envisioned as contributing to carcinogenic events 65 , , Progesterone and prolactin, which have been implicated in mammary tumorigenesis, both trigger RANKL expression in the mammary gland In one study using a hormone-triggered mammary tumor model in mice, specific deletion of RANK in mammary epithelial cells significantly delays tumor onset 65 , With respect to showing the contribution of local differentiation factors, in addition to chemotactic factors, to metastasis, it was shown that RANKL stimulation directly triggered metastasis of melanoma cell lines and breast cancer in patients in a manner that is independent of pro-osteoclastic activity Finally, important work to determine the key molecular pathways downstream of RANK signaling in metastatic tumor cells showed a correlation between metastatic potential and RANK-induced IKK-a activation As such, while initial efforts to characterize the role of RANKL—RANK—OPG in controlling osteoclastogenesis were ongoing, parallel efforts were underway showing that RANKL provided by T cells can significantly enhance immunity by promoting the survival and function of DCs, the most potent professional antigen-presenting cells, in the context of an immune response 4 , , Emerging understanding that key cellular regulators of the immune and bone systems were responsive to the same cytokine systems and derived from common progenitors was one of the key impetuses in developing a new field of study, osteoimmunology, which seeks to examine the interactions between the bone and immune systems.

Studies of RANK intracellular signaling pathways and regulatory mechanisms have further demonstrated the extent to which bone and immune cells overlap in these areas. Osteoimmunologic mechanisms are relevant to diseases including RA, periodontal disease, osteoporosis, osteoarthritis, multiple myeloma, and metastatic bone tumors, all of which are associated with bone breakdown RA is an autoimmune disease that is characterized by inflammation of the synovial joints, leading to severe structural damage including bone destruction.

At the same time, a recent fate mapping study showed that more a potently osteoclastogenic version of pathogenic Th17 cells are those that were previously Foxp3-expressing Tregs, but that converted phenotypes, and gained RANKL expression in response to synovial fibroblast-derived IL-6 Multi-photon microscopy was employed to perform intravital imaging of bone tissue in the context of RANKL-mediated OC activation, and it was showed that RANKL-expressing Th17 cells were able to stimulate mature but non-resorptive OCs to begin resorbing bone, suggesting that Thmediated bone pathology may not necessarily generate need OCs, but simply increase activity of mature resident OCs In another model system, a recent study showed that RANKL expression by B cells drive OC formation in an ovariectomy ovx model of osteoporosis, suggesting that B cells should be examined more closely in bone—immune cell interactions It is therefore clear that the cellular source of RANKL is critical to the context in which it is acting, and whether it primarily affects bone or immune cells.

RANKL is required for Tregs that prevent cytotoxic destruction of pancreatic beta islet cells in a mouse type-1 diabetes model , as well as for Treg-mediated control of a colitis model RANKL may promote peripheral immune tolerance. At the same time, another autoimmune disorder has recently been revealed, at a clinical level, to harbor a deleterious role for RANKL. Finally, an example of modulation of RANKL function at the level of central immune tolerance may have important clinical implications.

It was recently shown that mTEC inhibition via blockade of RANKL may represent a viable approach to boosting anti-tumor T cell responses by temporarily disrupting thymic negative selection to TSAs expressed by tumors Together these examples show that RANKL—RANK either activating or suppressive to an immune response depending on the context, and that while important roles for other cytokines have been identified [e. Figure 2. Osteoimmunology involves cross-regulation between cells of the bone and immune systems, and in some cases in the source of pathogenic conditions like rheumatoid arthritis RA.

The interface between the synovium and bone joints is where RA occurs, and where many cellular interactions typical of osteoimmunity have been characterized. The net effect of osteoimmune interactions is largely tallied according to increased or regulation of bone loss due to enhanced RANKL-mediated osteoclast OC differentiation from pre-OCs.

In addition to the usual sources of RANKL available to pre-OCs from bone-associated cells including bone stromal cells, osteoblasts OBs , and osteocytes, an inflammatory environment provides other sources. DC interactions with helper T cells influence their differentiation into subsets such as Th1, Th2, and Th At the same time, mitigation of potentially deleterious effects of osteoimmune interactions may be provided by secretion of OPG, which attenuates the potency of available RANKL.

The hundreds of studies it spurred have uncovered a much more vast biological network of regulation involving RANKL—RANK in and across other organ systems, and have as an additional benefit, demonstrated previously unknown ways in which organ systems interact and cross-regulate at a molecular level. Now that RANKL—RANK has been successfully harnessed for purposes of therapeutic treatments of osteoporosis, bone loss, and bone metastasis, it will be important to answer additional questions — specifically with respect to how RANK signaling is modulated, and how and on what cells RANKL is physiologically expressed under normal versus disease conditions — if therapeutic RANKL—RANK targeting is to be refined and potentially applied to additional disease conditions.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Cell 4 — Tumor necrosis factor family receptors regulating bone turnover: new observations in osteoblastic and osteoclastic cell lines.

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Question Importance. L 3 Question Complexity. L 4 Question Complexity. L 5 Question Complexity. L 1 Question Complexity. Sort by. All Videos 2 Podcasts 4. Login to View Community Videos. Michael Hughes. Orthobullets Team. Listen Now min. Team Orthobullets 4. Please login to add comment. J Bone Miner Res. Nat Genet. Hum Mol Genet. Cell Metab. Genes Dev. Arterioscler Thromb Vasc Biol. Circ Res. Rogers A, Eastell R: Circulating osteoprotegerin and receptor activator for nuclear factor kappaB ligand: clinical utility in metabolic bone disease assessment.

J Clin Endocrinol Metab. Genes Cells. Eur J Clin Invest. Takayanagi H: Mechanistic insight into osteoclast differentiation in osteoimmunology.

J Mol Med. Download references. You can also search for this author in PubMed Google Scholar. Correspondence to Brendan F Boyce. LX has no competing interests to declare.

Reprints and Permissions. Boyce, B. Arthritis Res Ther 9, S1 Download citation. Published : 29 June Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content. Search all BMC articles Search. Download PDF. Volume 9 Supplement 1. Introduction Bone serves multiple functions in vertebrates, including support for muscles, protection of vital organs and hematopoietic marrow, and storage and release of vital ions, such as calcium.

Regulation of osteoclast formation and activation Osteoclasts are multinucleated bone resorbing cells formed by cytoplasmic fusion of their mononuclear precursors, which are in the myeloid lineage of hematopoietic cells that also give rise to macrophages. RANKL RANKL is a type II homotrimeric transmembrane protein that is expressed as a membrane-bound and a secreted protein, which is derived from the membrane form as a result of either proteolytic cleavage or alternative splicing [ 14 ].

Osteoprotegerin OPG is expressed in many tissues apart from osteoblasts, including heart, kidney, liver, spleen, and bone marrow [ 17 ]. Figure 1. Full size image. Figure 2. Figure 3. References 1. PubMed Google Scholar Publication of the supplement has been supported by an unrestricted grant from Amgen Inc. View author publications. Additional information Competing interests BFB has received payment for consulting for Amgen as a member of their International Advisory Panel in