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Editorial |
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110
Address all correspondence and requests for reprints to: Steven L. Teitelbaum, M.D., Washington University School of Medicine, Department of Pathology and Immunology, Campus Box 8118, 660 South Euclid Avenue, St. Louis, Missouri 63110. E-mail: teitelbs{at}wustl.edu.
Regardless of the cause of acquired osteoporosis, it always represents an enhancement of the rate at which osteoclasts degrade the skeleton relative to the bone forming capacity of osteoblasts, thereby eventuating in negative bone balance. Thus, two general approaches to the treatment and prevention of the disease present themselves, namely inhibition of bone resorption or stimulation of bone formation. Despite the real promise of bone anabolism offered by intermittent PTH administration, most patients continue to be treated with antiresorptive agents. There is increasing consensus, in fact, that anabolic drugs offer a relatively short-term strategy to substantially increase bone mass with maintenance to be achieved by antiresorptives (1).
Estrogen deprivation is the key event in the pathogenesis of postmenopausal osteoporosis. Thus, hormone replacement, whose principal effect is to dampen bone resorption, had, until relatively recently, been the mainstay of treating the disease. With the realization that supplemental estrogen carries substantial extraskeletal risks, its acceptance as an antiosteoporotic agent has diminished. Fortunately, the bisphosphonates have been effective substitutes. Similar to estrogen, however, concerns about prolonged bisphosphonate therapy are emerging.
Bone is a dynamic tissue, consistently remodeled by the tethered recruitment of osteoclasts and osteoblasts. In this scenario, the prior resorptive activity of osteoclasts, at a specific site, recruits osteoblasts to synthesize bone at the same location. It is important to realize, however, that remodeling represents the coupled appearance of osteoclasts and osteoblasts but not necessarily equal rates of bone degradation and formation. For example, both bone resorption and formation are enhanced in postmenopausal osteoporosis or continuous PTH administration, but the loss of skeletal mass that occurs in both circumstances is reflective of the dominance of the osteoclast. On the other hand, intermittently administered PTH also stimulates recruitment of both osteoclasts and osteoblasts, but the attendant increase in bone density, in this case, establishes osteoblast supremacy. In fact, development of strategies to suppress bone resorption while maintaining formation remains a challenge in the design of antiosteoporotic agents.
A principal role of remodeling is probably conservation of skeletal strength by replacing effete, older bone with newly synthesized bone. Thus, events that profoundly suppress the remodeling process may yield brittle bones. Examples of such adynamic, fragile skeletons are encountered in some patients with chronic renal failure. Such individuals have proven more difficult to treat than those with more typical renal osteodystrophy, in which bone remodeling is accelerated due to hyperparathyroidism.
Unfortunately, evidence is emerging that the remodeling-suppressive effects of long term bisphosphonate therapy eventuate in adynamic, fragile bone, resistant to both fracture repair (2) and the anabolic effects of intermittent PTH administration (3). In fact, bisphosphonates given to children may suppress osteoclast activity profoundly enough to cause osteopetrosis (4). These seemingly negative effects of bisphosphonates are of particular concern because the drugs are stored in the skeleton for decades and are continuously mobilized by the osteoclast. As a result, there is substantial interest in alternative, short duration antiresorptive strategies. In this issue of JCEM, Murphy et al. (5) report that blockade of the 
vß3 integrin on osteoclasts offers a promising approach.
The osteoclast is a member of the monocyte/macrophage family whose differentiation into its bone resorptive phenotype is mediated by receptor activator of nuclear factor 
B ligand (RANKL), a member of the TNF superfamily. The discovery of the unique osteoclastogenic capacity of RANKL is clearly the key event delineating the biology of the cell (6). Furthermore, the cytokine enables generation of virtually pure populations of osteoclasts and their committed precursors and, therefore, performance of precise biochemical and molecular experiments. These studies have yielded critical insights as to how the osteoclast differentiates and resorbs bone and have identified regulatory molecules as candidate mechanistic therapeutic targets.
We know that osteoclastic resorption requires creation of a microenvironment at the cell/bone interface that is isolated from the general extracellular space (7). Formation of this microenvironment is actually initiated by the cell’s contact with bone, thus prompting matrix-derived signals to enter the osteoclast, leading to polarization of specific organelles toward the bone surface. The osteoclast’s electrogenic proton pump (H+ATPase), which is similar, but probably not identical, to its counterpart in the renal tubule, is among the most important molecules to polarize, after which it mediates massive extracellular proton transport and acidifies the resorptive microenvironment to a pH of approximately 4.5. Intracellular pH is maintained by a Cl–/HCO3– exchanger on the antiresorptive surface of the cell and anion excess is prevented by a bone-apposed Cl– channel. The net result of these activities is generation of HCl in the isolated osteoclast/bone interface that mobilizes the mineral phase of bone exposing its organic matrix, which is subsequently degraded by the lysosomal collagenolytic enzyme, cathepsin K. The critical role of most of these molecules in bone resorption is established both biochemically and genetically in mouse and/or man. In fact, mutation of the osteoclast proton pump is the most common known cause of human osteopetrosis. Furthermore, RANKL-blocking monoclonal antibodies (8) and small molecule cathepsin K inhibitors (9) are in clinical trial as anti-bone resorptive agents.
These findings indicate that formation of the extracellular resorptive microenvironment is central to physiological bone degradation which, in turn, depends upon the capacity of the osteoclast to recognize and attach to bone. Thus, integrins that are the principal cell-matrix attachment molecules present themselves as antiresorptive therapeutic targets.
Integrins are transmembrane heterodimers consisting of - and ß-subunits with long extracellular and relatively short intracellular domains. These /ß-complexes consist of a promiscuous and a relatively monogamous partner and each integrin family is named by the former. Thus, vß3, which is the dominant osteoclast integrin, is a member of the v family. vß3 expression is a marker of the osteoclast phenotype, as it is absent on its macrophage precursors but is progressively induced by RANKL (10). The arrest of osteoclast function in vitro and in vivo by soluble ligands that compete for vß3 suggested that the integrin is central to physiological bone resorption (11). On the other hand, because the vß3’s natural ligand, namely the Arg-Gly-Asp (RGD) amino acid motif, is also recognized by other integrins, ultimate proof that vß3 is a molecule central to osteoclast function came with deletion of the ß3 gene in mice that obviates expression of the heterodimer (12). These animals generate abnormal and ineffectual osteoclasts with diminished capacity to resorb bone. As such, bone resorption is attenuated in vivo and skeletal mass progressively increases with age.
Integrins were initially viewed as cell attachment molecules and there was little appreciation of their capacity to transmit matrix-derived intracellular signals. We now know that the intracellular domain of the ß3 integrin, in the osteoclast, activates a host of signaling molecules including Src, Syk, and Pyk2 as well as a number of cytoskeletal proteins (13). In fact, there is reason to suspect that the principal role of vß3 is to convey signals derived upon contact with bone, which leads to organization of the osteoclast cytoskeleton and thus formation of the isolated resorptive microenvironment. This posture is buttressed by the capacity of occupied vß3 to activate the Rac family of GTPases (14) and the guanine nucleotide exchange factor, VAV3 (15), each of which is pivotal to osteoclast cytoskeletal organization.
The capacity of competitive vß3 ligands to arrest bone resorption positioned the integrin as a candidate anti-bone resorptive therapeutic target. Thus, in 1997, Engleman et al. (16) documented that a small peptide mimetic of the RGD motif arrests bone loss in the ovariectomized rat, establishing proof of concept for vß3 targeting.
vß3 is abundantly expressed by endothelial cells in states of inflammation and tumor-associated neovascularization. In physiological circumstances, however, the ß3 integrin subunit is largely confined to osteoclasts, the placenta, and platelets. Although in osteoclasts and the placenta, ß3 associates with v, in the platelet it partners with a different -integrin subunit, namely glycoproteinIIb, and thus serves as an essential mediator of coagulation. In fact, loss-of-function ß3 mutations in humans cause the bleeding dyscrasia, Glanzmann’s thrombasthenia. As expected, ß3 integrin-knockout mice suffer from the same platelet defect (12). Although the specific Glanzmann’s mutations in the ß3 integrin cytoplasmic domain, S752P, arrest both osteoclast and platelet function, for reasons unknown, Y747F/Y752F impact only the platelet (17). In any event, meaningful targeting of vß3 requires generating a competitive molecule selective for the osteoclast integrin while sparing the platelet, and such has been achieved (18).
In the present study, Murphy et al. (5) administered placebo or an vß3 small molecule inhibitor at three dosing schedules for 1 yr to postmenopausal women and, although no comparative drugs were included in the study, the authors noted an increase in spinal bone mineral density approximating that achieved by available bisphosphonates. These are encouraging findings and in keeping with the resistance of the ß3 integrin-knockout mouse to experimental postmenopausal osteoporosis. Furthermore, because tumor-induced osteolysis is arrested in experimental animals by vß3 blockade (19), these observations justify studies in patients at high risk for skeletal metastasis such as those with advanced breast cancer.
On the other hand, the results should be considered with caution. In the first instance, the candidate drug suppresses bone formation as well as resorption and, thus, carries the possibility of promoting adynamic bone. The short duration of action and the fact that the inhibitor, unlike bisphosphonates, is not stored in bone is a distinct theoretical advantage, however, as its effects would be rapidly reversible. Furthermore, possible extraskeletal complications must be addressed. Although skin rash and urticaria appear to be the most obvious adverse event in this study, there is evidence in experimental animals that absence of vß3 function may promote atherosclerosis and pulmonary inflammation (20). The fact that the integrin is up-regulated during myocardial ischemia also raises the possibility that it participates in the cardiac repair process (21). Notwithstanding these uncertainties, the vß3 integrin stands as a paradigm of a mechanistically identified mediator of osteoclast function and joins other such molecules, which are active therapeutic targets. The challenge will be to distinguish the efficacy and safety of each.
Footnotes
Abbreviation: RANKL, Receptor activator of nuclear factor B ligand.
Received February 15, 2005.
Accepted March 1, 2005.
References
Vß3 integrin antagonist, on markers of bone turnover and bone mineral density in postmenopausal osteoporotic women. J Clin Endocrinol Metab 90:2022–2028B ligand (RANKL)-directed osteoclast differentiation. Exp Cell Res 289:368–377[CrossRef][Medline]
vß3 integrin collaborate during osteoclast differentiation. J Clin Invest 111:749–758[CrossRef][Medline]
vß3 integrin inhibits bone resorption in vitro and prevents osteoporosis in vivo. J Clin Invest 99:2284–2292[Medline]
vß3 integrin suppresses MDA-MB-435 skeletal metastasis. Clin Exp Metastasis 21:119–128[CrossRef][Medline]
vß3), activation of the matrix metalloproteinase induction system, and subsequent development of coronary vasculopathy. Circulation 105:1955–1961This article has been cited by other articles:
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