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Minireview: The OPG/RANKL/RANK System

Endocrine Research Unit, Division of Endocrinology, Metabolism, and Nutrition, Mayo Clinic and Foundation, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Sundeep Khosla, M.D., Mayo Clinic, 200 First Street SW, 5-194 Joseph, Rochester, Minnesota 55905. E-mail: khosla.sundeep{at}mayo.edu

	Abstract

Top Abstract Introduction OPG: The Key to... Identification of the Ligand... RANK—The Final Piece of... A Complete Picture of... Implications for the... Conclusions References

 
The identification of the OPG/RANKL/RANK system as the dominant, final mediator of osteoclastogenesis represents a major advance in bone biology. It ended a long-standing search for the specific factor produced by preosteoblastic/stromal cells that was both necessary and sufficient for osteoclast development. The initial cloning and characterization of OPG as a soluble, decoy receptor belonging to the TNF receptor superfamily was the first step that eventually led to an unraveling of this system. Soon thereafter, the molecule blocked by OPG, initially called OPG-ligand/osteoclast differentiating factor (ODF) and subsequently RANKL, was identified as the key mediator of osteoclastogenesis in both a membrane-bound form expressed on preosteoblastic/stromal cells as well as a soluble form. RANKL, in turn, was shown to bind its receptor, RANK, on osteoclast lineage cells. The decisive role played by these factors in regulating bone metabolism was demonstrated by the findings of extremes of skeletal phenotypes (osteoporosis vs. osteopetrosis) in mice with altered expression of these molecules. Over the past several years, work has focused on identifying the factors regulating this system, the signaling mechanisms involved in the RANKL/RANK pathway, and finally, potential alterations in this system in metabolic bone disorders, from the extremely common (i.e. postmenopausal osteoporosis) to the rare (i.e. familial expansile osteolysis).

	Introduction

Top Abstract Introduction OPG: The Key to... Identification of the Ligand... RANK—The Final Piece of... A Complete Picture of... Implications for the... Conclusions References

 
THE PAST 15 yr have witnessed an explosion in the field of bone biology. Indeed, the scientific view of bone has evolved from considering it as a relatively uninteresting scaffold for the rest of the body to an extremely complex organ regulated by a host of systemic and local factors. The landscape of bone biology over this time period has also been marked by a number of key discoveries that led to opening up entirely new areas for investigation. These include (among others) the identification of sex steroid receptors in bone cells (1, 2); the cloning and characterization of PTH-related peptide (PTHrP) as the major factor responsible for the syndrome of humoral hypercalcemia of malignancy (3, 4) and as an important locally active cytokine in bone, cartilage, and other tissues (5); the identification of core binding factor 1 (Cbfa1) as the (or at least a) master gene controlling osteoblast differentiation (6, 7); and the important role of apoptosis in regulating osteoblast and osteoclast number (8). Certainly, the identification and characterization of the OPG/RANK-L/RANK system, which began with a seminal paper published in 1997 (9), is a major addition to this list of momentous events in bone biology.

	OPG: The Key to the Puzzle

Top Abstract Introduction OPG: The Key to... Identification of the Ligand... RANK—The Final Piece of... A Complete Picture of... Implications for the... Conclusions References

 
OPG was discovered independently by two groups, although the manner in which these groups identified it differed markedly. The Amgen, Inc. group in the US initially described a fascinating molecule that they had happened upon as part of a project characterizing cDNAs in rat intestine (9). Indeed, it is unlikely that this group was actually searching for OPG, and the project apparently focused on identifying TNF receptor-related molecules that may potentially have therapeutic utility. One particular cDNA encoded a truncated TNF receptor-like protein that contained no hydrophobic transmembrane-spanning sequences. This clone would have been no different from other interesting cDNAs were it not for the fact that transgenic mice overexpressing this gene had a remarkable skeletal phenotype—they had marked osteopetrosis. Further analysis of these mice revealed that the osteopetrosis was due to a profound decrease in osteoclasts, indicating that OPG (short for osteoprotegerin, i.e. to protect bone) clearly must play a key role in regulating osteoclastogenesis.

Independently, the Snow Brand Milk Group in Japan reported the identification of the identical molecule (10), but the route by which they got there was clearly different. In 1981, Rodan and Martin (11) had proposed a novel hypothesis wherein the osteoblast played a central role in mediating the hormonal control of osteoclastogenesis and bone resorption. Subsequently, there was accumulating experimental evidence that osteoblastic/stromal cells were essential for in vitro osteoclastogenesis and that these cells regulated osteoclast differentiation both by producing soluble factors and also by signaling to osteoclast progenitors through cell-to-cell contact (12, 13). Thus, the Snow Brand group was systematically searching for both osteoclast stimulatory and inhibitory factors. Indeed, they had previously reported the purification of an osteoclastogenesis inhibitory factor (OCIF) from the conditioned medium of human embryonic fibroblasts (14). They subsequently used the partial protein sequence to isolate cDNA clones encoding OCIF, which turned out to be identical with the protein that had been reported by the Amgen, Inc. group (9).

These initial reports were followed by numerous studies further characterizing OPG. It was found to be initially synthesized as a 401 amino acid peptide, with a 21-amino acid propeptide that was cleaved, resulting in a mature protein of 380 amino acids (9, 10). As noted earlier, in contrast to all other TNF receptor superfamily members, OPG lacked transmembrane and cytoplasmic domains and was secreted as a soluble protein. The N-terminal region contained four cysteine-rich domains (D1–D4) and was most closely related to TNF receptor-2 and CD40. The C-terminal region contained two death domain homologous regions (D5 and D6) as well as a region (D7) containing a heparin binding site and a cysteine residue necessary for homodimerization (9, 10, 15).

OPG mRNA was found to be expressed in a number of tissues, including lung, heart, kidney, liver, stomach, intestine, brain and spinal cord, thyroid gland, and bone (9, 10). Because the major biologic action of OPG described to date has been to inhibit osteoclast differentiation and activity (9, 10), the potential role of OPG in these other tissues remains to be established. However, mice with targeted ablation of OPG not only develop severe osteoporosis due to markedly increased osteoclast formation and subsequent bone resorption (16, 17), but also have profound calcification of the large arteries, marked intimal and medial proliferation, and partial aortic dissection by the age of 4 months (16). Thus, OPG likely also plays a significant role in the vasculature, and indeed, a recent study has found that OPG may be an important survival factor for endothelial cells (18).

	Identification of the Ligand for OPG (OPG-L), RANKL

Top Abstract Introduction OPG: The Key to... Identification of the Ligand... RANK—The Final Piece of... A Complete Picture of... Implications for the... Conclusions References

 
As soon as OPG was characterized, it became clear that it likely was going to be the key to identifying the long-sought osteoclast differentiation factor expressed on osteoblastic/stromal cells that was essential for osteoclast development. Indeed, soon after the identification of OPG, both groups had used expression cloning using OPG as a probe and had identified its ligand (initially termed OPG-L/ODF) (19, 20), which turned out to be identical with two previously known members of the TNF ligand family—TNF-related activation-induced cytokine (TRANCE) (a gene induced by activation of the T cell receptor) and RANKL, a factor known to stimulate dendritic cells (21, 22).

Human RANKL is a 317-amino acid peptide that has approximately 30% homology to the TNF-related apoptosis-inducing ligand and to CD40, and approximately 20% homology to Fas ligand (19, 20, 21, 22). It has now been shown to exist in two forms: a 40- to 45-kDa cellular, membrane-bound form and a 31-kDa soluble form derived by cleavage of the full-length form at position 140 or 145 (19). RANKL mRNA is expressed at highest levels in bone and bone marrow, as well as in lymphoid tissues (lymph node, thymus, spleen, fetal liver, and Peyer’s patches) (19, 20, 21, 22). Its major role in bone is the stimulation of osteoclast differentiation (18, 19), activity (19), and inhibition of osteoclast apoptosis (23). Indeed, in the presence of low levels of macrophage-colony stimulating factor (M-CSF), RANKL appears to be both necessary and sufficient for the complete differentiation of osteoclast precursor cells into mature osteoclasts (19, 20). In addition, it is clear that RANKL (or, as it was originally identified, TRANCE) has a number of effects on immune cells, including activation of c-Jun N-terminal kinase (JNK) in T cells (21), inhibition of apoptosis of dendritic cells (24), induction of cluster formation by dendritic cells, and effects on cytokine-activated T cell proliferation (22).

Consistent with these findings, RANKL knockout mice have severe osteopetrosis with defects in tooth eruption (25). They also have a complete absence of osteoclasts. In addition, they exhibit defects in early differentiation of T and B cells, lack lymph nodes, have defects in thymic differentiation, but have a normal splenic structure and Peyer’s patches (25). A somewhat unexpected finding in these mice is that they also have defects in mammary gland development (26). In particular, they fail to form lobulo-alveolar structures during pregnancy, resulting in death of the newborns (26).

	RANK—The Final Piece of the Puzzle

Top Abstract Introduction OPG: The Key to... Identification of the Ligand... RANK—The Final Piece of... A Complete Picture of... Implications for the... Conclusions References

 
With the identification of the ligand for OPG as being identical with TRANCE/RANKL, the final piece of the puzzle fell into place relatively easily, because the receptor for this had already been identified as RANK (22). Hsu et al. (27) subsequently demonstrated that RANK mRNA was highly expressed by isolated bone marrow-derived osteoclast progenitors and by mature osteoclasts in vivo and that transgenic mice expressing a soluble RANK-Fc fusion protein had severe osteopetrosis and a skeletal phenotype similar to OPG transgenic mice. The ultimate proof that RANK expressed on preosteoclastic cells was the sole receptor on these cells for RANKL came with the demonstration that RANK knockout mice had profound osteopetrosis due to an absence of osteoclasts (28). Moreover, osteoclastogenesis could be initiated in these mice by transfer of the RANK cDNA back into hematopoietic precursors. Interestingly, similar to the RANKL knockout mice, RANK knockout mice also lacked peripheral lymph nodes and had defective B and T cell maturation but differed from the RANKL knock out mice in having normal thymic development (28).

Human RANK is a 616-amino acid peptide, with a 28-amino acid signal peptide, an N-terminal extracellular domain, a short transmembrane domain of 21 amino acids, and a large C-terminal cytoplasmic domain (22). It is expressed primarily on cells of the macrophage/monocytic lineage, including preosteoclastic cells, T and B cells, dendritic cells, and fibroblasts (22, 27). The RANKL/RANK signaling pathway has also been extensively studied in recent years. Thus, RANK activation by RANKL is followed by its interaction with TNF receptor-associated (TRAF) family members, activation of nuclear factor (NF)-B and c-Fos, JNK, c-src, and the serine/threonine kinase Akt/PKB (22, 27). Consistent with these findings, mice with various components of this signaling pathway ablated [i.e. TRAF-6 (29) or NF-B1/NF-B2 (30)] have an osteopetrotic phenotype.

	A Complete Picture of Osteoclastogenesis Emerges

Top Abstract Introduction OPG: The Key to... Identification of the Ligand... RANK—The Final Piece of... A Complete Picture of... Implications for the... Conclusions References

 
The unraveling of the OPG/RANKL/RANK system, which occurred over a span of approximately 2 yr or less, solved a long standing unresolved question in bone biology, namely the precise mechanisms by which preosteoblastic/stromal cells controlled osteoclast development. Given what we know about the process of bone remodeling, it is easy to understand why these early osteoblastic cells need to have the critical say in whether osteoclasts are formed or not. Thus, bone is constantly being resorbed and formed at specific sites in the skeleton, termed basic multicellular units. The process begins by migration of osteoclasts to these sites (activation), resorption of a packet of bone by these cells, a reversal phase characterized by apoptosis of the osteoclasts, followed by a phase of bone formation by newly formed osteoblasts. As such, it makes sense that the critical, initial step in this process, the development of osteoclasts, should be under the control of preosteoblastic/stromal cells: this ensures that the processes of bone resorption and formation will be tightly coupled, allowing for a wave of bone formation to follow each cycle of bone resorption, thus maintaining skeletal integrity. Further coupling between osteoblastogenesis and osteoclastogenesis is ensured by the fact that the osteoblast differentiation factor, cbfa1, is necessary for adequate expression of the osteoclast differentiation factor, RANKL, on the surface of preosteoblastic/stromal cells (31).

Figure 1 summarizes the current picture of the control of osteoclastogenesis that has emerged in the post OPG/RANKL/RANK era. RANKL, expressed on the surface of preosteoblastic/stromal cells, binds to RANK on the osteoclastic precursor cells. M-CSF, which binds to its receptor, c-Fms, on preosteoclastic cells, appears to be necessary for osteoclast development because it is the primary determinant of the pool of these precursor cells (32). RANKL, however, is critical for the differentiation, fusion into multinucleated cells, activation, and survival of osteoclastic cells. OPG puts a brake on the entire system by blocking the effects of RANKL. A number of proresorptive cytokines, such as TNF- and IL-1, modulate this system primarily by stimulating M-CSF production (thereby increasing the pool of preosteoclastic cells) and by directly increasing RANKL expression (33). In addition, a number of other cytokines and hormones, such as TGF-ß (increased OPG production) (34), PTH (increased RANKL/decreased OPG production) (35), 1,25-dihydroxyvitamin D₃ (increased RANKL production) (36), glucocorticoids (increased RANKL/decreased OPG production) (37), and estrogen (increased OPG production) (38, 39) exert their effects on osteoclastogenesis by regulating osteoblastic/stromal cell production of OPG and RANKL. However, not all regulation of the osteoclast is exclusively via the osteoblast because calcitonin acts directly on osteoclastic cells (40), and estrogen has been shown to induce apoptosis of osteoclasts (41) as well as inhibit osteoclast differentiation by interfering with RANK signaling, principally RANKL-induced JNK activation and c-Jun activity and expression (42, 43). Moreover, TGF-ß can also stimulate RANK expression on preosteoclastic cells, and thus enhance osteoclastic sensitivity to RANKL (44).

View larger version (43K): [in this window] [in a new window]   Figure 1. Current understanding of preosteoblastic/stromal cell regulation of osteoclastogenesis. See text for details.

	Implications for the Pathogenesis and Treatment of Disorders of Bone Metabolism

Top Abstract Introduction OPG: The Key to... Identification of the Ligand... RANK—The Final Piece of... A Complete Picture of... Implications for the... Conclusions References

 
As with any breakthrough in basic science, the onus rapidly falls on the clinical investigator to translate the findings into a better understanding of disease as well as potentially new treatment approaches. This process has just begun for the OPG/RANKL/RANK system and will likely accelerate as the tools to assess gene expression in smaller and smaller amounts of biological samples with greater reliability continue to evolve.

The disorders most clearly related to alterations in this system are familial expansile osteolysis, a rare autosomal dominant disorder characterized by focal areas of enhanced bone resorption, and familial Paget’s disease, both of which are due to mutations in the signal peptide region of the RANK protein (46). These mutations may lead to an accumulation of defective RANK translation products in the secretion pathway, resulting perhaps in receptor self-association and increased constitutive RANK signal transduction.

The role of the OPG/RANKL/RANK system in the pathogenesis of more common disorders, such as postmenopausal or age-related osteoporosis, remains controversial. As noted earlier, estrogen does increase OPG production by osteoblastic (38) and marrow stromal cells (39). However, serum OPG levels are, if anything, higher in postmenopausal women with osteoporosis and increased bone turnover (47), perhaps as a homeostatic mechanism limiting their more rapid bone loss. In addition, although OPG production by marrow stromal cells appears to decline with age (48), serum OPG levels have consistently been found to increase with age in women and in men (47).

Although depressed bone formation is the major abnormality in glucocorticoid-induced osteoporosis (50), bone resorption is often increased or at the least, inappropriately normal for the depressed level of bone formation (50). Because glucocorticoids are potent inhibitors of OPG production and also stimulate RANKL levels in osteoblastic cells (37), this decrease in the OPG/RANKL ratio may well account for an enhanced ability of preosteoblastic cells (reduced in number as they may be) to support osteoclast development, leading to the observed marked imbalance between bone formation and resorption and rapid bone loss in this condition.

As noted earlier, PTH increases RANKL and decreases OPG expression by osteoblastic cells, leading to a net catabolic effect on bone (35). However, intermittent PTH clearly has anabolic effects on bone, and recent data indicate that, in contrast to continuous exposure, intermittent exposure of marrow stromal cells to PTH does not lead to a significant alteration in the OPG/RANKL ratio, while still stimulating markers of bone formation (50). Thus, differential effects of PTH on the OPG/RANKL system, depending on whether it is administered continuously or intermittently, may well explain the catabolic vs. anabolic effects of PTH on bone.

In addition to the RANK activating mutations in familial Paget’s disease, bone marrow stromal cells in Paget’s disease have been shown to have enhanced RANKL expression, and preosteoclastic cells from affected lesions have increased sensitivity to RANKL (51). This combination of abnormalities may explain, at least in part, the increased numbers of osteoclasts in Pagetic bone. Finally, activated T cells (as in rheumatoid arthritis) have increased levels of RANKL expression (52) and RANKL, in the presence of M-CSF, can induce synovial macrophages to differentiate into osteoclastic bone-resorbing cells (53), thus potentially leading to the periarticular bone loss commonly seen in various forms of inflammatory arthritis.

OPG or other components of this system may also have therapeutic utility in conditions associated with accelerated bone resorption, including skeletal metastases from multiple myeloma or other tumors, and postmenopausal osteoporosis. Indeed, OPG has been shown to block skeletal destruction and pain in a mouse model of sarcoma-induced bone destruction (54). In addition, a RANK-Fc fusion protein was effective in suppressing bone resorption and hypercalcemia in a murine model of humoral hypercalcemia of malignancy due to xenografts of human lung cancer (55). Finally, a single dose of a OPG-Fc fusion protein resulted in a profound (by up to 80%) and sustained (for up to 3 wk) suppression of bone resorption in postmenopausal women (56). However, whether these approaches will translate into viable new therapies for these disorders or whether alternate approaches (such as the development of small molecules to locally regulate OPG/RANKL production in the bone microenvironment) will be needed remains to be seen.

	Conclusions

Top Abstract Introduction OPG: The Key to... Identification of the Ligand... RANK—The Final Piece of... A Complete Picture of... Implications for the... Conclusions References

 
The pace of developments resulting in an unraveling of the OPG/RANKL/RANK system over the past few years, leading to a nearly complete understanding of osteoblastic regulation of osteoclastogenesis, is truly breathtaking. In addition to providing fundamental insights in bone biology, these events have identified an entirely new set of candidate factors that may be involved in the pathogenesis of a number of rare and common metabolic bone diseases. Although only time will tell whether these advances will translate into new therapeutic approaches, clearly the detailed characterization of this system has opened up entirely new areas for basic and clinical investigation in bone biology and diseases, respectively.

	Acknowledgments

 
I would like to thank Drs. B. L. Riggs and T. C. Spelsberg for helpful suggestions and comments.

	Footnotes

 
This work was supported by Research Grant AG04875 from the National Institute on Aging, United States Public Health Service.

Abbreviations: Cbfa1, Core binding factor 1; JNK, c-Jun N-terminal kinase; M-CSF, macrophage-colony stimulating factor; NF, nuclear factor; OCIF, osteoclastogenesis inhibitory factor; OPG-L, ligand for OPG; PTHrP, PTH-related peptide; TRAF, TNF receptor-associated family; TRANCE, TNF-related activation-induced cytokine.

Received August 21, 2001.

Accepted for publication August 31, 2001.

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