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© 2001 American Society for Clinical Oncology
Biology of Osteoclast Activation in CancerByFrom the University of Texas Health Science Center at San Antonio and Audie Murphy Veterans Administration Hospital, San Antonio, TX. Address reprint requests to G. David Roodman, MD, PhD, Research/Hematology (151), Audie Murphy Veterans Administration Hospital, 7400 Merton Minter Blvd, San Antonio, TX 78284; email: roodmangd{at}msx.upmc.edu
ABSTRACT: Bone is a frequent site of cancer metastasis. Bone metastases can result in bone destruction or new bone formation. Bone destruction is mediated by factors produced or induced by tumor cells that stimulate formation and activation of osteoclasts, the normal bone-resorbing cells. Local bone destruction also occurs in patients with osteoblastic metastases and may precede or occur simultaneously with increased bone formation. Several factors, including interleukin (IL)-1, IL-6, receptor activator of NF-kappaB (RANK) ligand, parathyroid hormone-related protein (PTHrP), and macrophage inflammatory protein-1-alpha (MIP-1  ), have been implicated as factors that enhance osteoclast formation and bone destruction in patients with neoplasia. PTHrP seems to be the major factor produced by breast cancer cells that induces osteoclast formation through upregulation of RANK ligand. Enhanced RANK ligand expression also plays an important role in bone destruction in patients with myeloma. RANK ligand can act to enhance the effects of other factors produced by myeloma cells or in response to myeloma cells, such as MIP-1 and/or IL-6, to induce osteoclast formation. Understanding of the molecular mechanisms responsible for osteoclast activation in osteolytic metastases should lead to development of novel therapeutic approaches for this highly morbid and potentially fatal complication of cancer.
THE OSTEOCLAST IS the primary bone-resorbing cell in both normal and pathologic states. Increased osteoclastic bone resorption results from both increased osteoclast formation and activation of preformed osteoclasts to resorb bone. In patients with bone metastases, osteolytic bone destruction can result in severe bone pain, pathologic fractures, hypercalcemia, and nerve compression syndromes. Several tumors show a high predilection for bone, including renal cancer, lung cancer, thyroid cancer, prostate cancer, and breast cancer. Coleman and Rubens1 have reported that nearly 70% of patients dying with breast cancer have bone metastases. In addition to having osteolytic metastases, patients can also have osteoblastic metastases or mixed osteolytic/osteoblastic metastases, with osteoblastic metastases predominating in patients with prostate cancer. Although in vitro studies have shown that breast cancer cells can resorb bone,2 the overwhelming majority of evidence3 demonstrates that the primary mechanism responsible for bone destruction in patients with cancer is tumor-mediated stimulation of osteoclastic bone resorption. Tumor products can either stimulate osteoclast formation locally in the bone microenvironment or systemically through production of hormones such as parathyroid hormone-related protein (PTHrP), the mediator of the humoral hypercalcemia of malignancy.4,5 Other factors produced by tumors that can stimulate osteoclastic bone resorption include interleukin (IL)-6, IL-1, tumor necrosis factor-alpha (TNF ), and macrophage inflammatory protein-1-alpha (MIP-1). In this review, the mechanisms underlying increased osteoclast formation and activation in neoplasia and the factors responsible for this activation are discussed.
The osteoclast is hematopoietic in origin and derived from cells in the monocyte-macrophage lineage which then fuse to form inactive osteoclasts. Osteoclasts are activated to resorb bone and then eventually undergo apoptosis (Fig 1). Both locally produced cytokines and systemic hormones can regulate normal osteoclast formation.6 Phenotypic characteristics of osteoclasts include that they are large multinucleated cells that contract in response to calcitonin, react strongly with the 23c6 monoclonal antibody that identifies the osteoclast vitronectin receptor, express high levels of tartrate-resistant acid phosphatase, a marker enzyme for osteoclasts, and resorb bone.
The bone microenvironment plays a critical role in osteoclast formation. Udagawa et al7 and Takahashi et al8 reported that coculture of spleen cells or marrow cells as a source of osteoclast precursors with marrow stromal cells or osteoblasts induced osteoclast formation. However, stromal cell lines developed from mouse bone marrow displayed heterogeneity in their capacity to support osteoclastogenesis.9 Stromal cells or osteoblasts that induced osteoclast formation produced macrophage colony-stimulating factor (M-CSF), whereas marrow stromal cells or osteoblasts from op/op mice that lack M-CSF do not support osteoclast differentiation.10 Soluble M-CSF could not replace the requirement for stromal cells in this coculture system, which suggests that membrane-bound M-CSF or other factors produced by marrow stromal cells or osteoblasts were absolutely required for murine osteoclast development from precursors. Recently, a factor produced by marrow stromal cells and osteoblasts has been identified that is critical to osteoclast formation and can replace stromal cells in coculture systems to induce osteoclast formation by spleen cells. This factor, receptor activator of NF-kappaB (RANK) ligand, is a new member of the TNF gene family.11,12 It is also called TRANCE, osteoclast differentiation inducing factor, or osteoprotegerin (OPG) ligand. RANK ligand activates c-jun terminal kinase and signals through NF-kappaB. Yasuda et al12 and Hofbauer and Heufelder13 have shown that most osteotropic factors induce osteoclast formation and act indirectly by binding to marrow stromal cells, which in turn express increased levels of RANK ligand on their surface. RANK ligand then binds the RANK receptor on osteoclast precursors and induces osteoclast formation (Fig 2). A soluble form of RANK ligand has been engineered which induces large numbers of osteoclasts when added to spleen cells or granulocyte-macrophage colony-forming unit–derived cells in the presence of M-CSF and dexamethasone. Furthermore, the importance of RANK ligand in osteoclast formation has been shown by the techniques of homologous recombination, in which the absence of RANK ligand expression in mice results in severe osteopetrosis and absence of osteoclasts.14 Similarly, overexpression of RANK ligand in transgenic mice induces severe osteoporosis. RANK ligand activity can be blocked by the soluble decoy receptor, OPG. OPG, also called osteoclastogenesis inhibitory factor, is a member of the TNF receptor superfamily that has been identified recently.15,16 In vitro and in vivo osteoclast differentiation from precursor cells is blocked in a dose-dependent manner by recombinant OPG. OPG is produced by most cell types and seems to block the fusion/differentiation stage of osteoclast differentiation, rather than the proliferative phase, by binding to RANK ligand. OPG also binds to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). Workers at both Amgen (Thousand Oaks, CA) and Snow Brand Milk (Tochigi, Japan) have shown that overexpression of OPG in transgenic mice results in severe osteopetrosis, whereas absence of OPG induces osteopenia.17 Thus, RANK ligand and OPG are important regulators produced by the marrow microenvironment, and the ratio of RANK ligand to OPG regulates osteoclast formation and osteoclast activity.
MECHANISMS OF OSTEOCLASTIC BONE RESORPTION Osteoclasts resorb bone by secreting proteases that dissolve the matrix and acid that releases bone mineral into the extracellular space under the ruffled border (Fig 3). Osteoclast secretion of hydrogen ion can be modulated by regulators of osteoclastic bone resorption. For example, parathyroid hormone (PTH) and prostaglandin E (PGE) increase acid secretion by osteoclasts,18 whereas calcitonin decreases acid secretion. Microelectrode-based pH measurements at the ruffled border have shown pH levels as low as 3 to 4.19 Acid secretion by the osteoclast requires a proton pump. At least three different types of proton pumps have been implicated in the acidification process, but the strongest evidence suggests that a vacuolar type proton pump, which is similar to the kidney H+-ATPase, is involved in osteoclastic bone resorption.20 This proton pump appears to transport protons against a concentration gradient. Protons are supplied for the proton pump by the action of several enzymes, including carbonic anhydrase II.21 The critical importance of carbonic anhydrase II in the osteoclast has been shown by studies in patients with a congenital absence of this enzyme and osteopetrosis.22 Similarly, the carbonic anhydrase inhibitor acetozolamide23 can inhibit osteoclastic bone resorption. Lysosomal hydrolases that are active at acid pH resorb the organic matrix. The osteoclast contains high levels of matrix metalloproteinase (MMP)-9 that may act in concert with collagenase to degrade the collagen matrix. The recent discovery of cathepsin K, a cysteine proteinase that is highly expressed in osteoclasts that can degrade collagen in addition to cathepsins B and L, suggests that the osteoclast secretes enzymes which may directly digest collagen.
PATHOPHYSIOLOGY OF OSTEOCLAST ACTIVATION IN BREAST CANCER Bone destruction in patients with breast cancer results from local production of factors secreted by the tumor cells which stimulate osteoclast formation. Osteoclastic bone resorption in turn then releases growth factors from the bone matrix which further stimulate tumor growth. This reciprocal interaction between breast cancer cells and osteoclasts results in a "vicious cycle" in which breast cancer cells stimulate osteoclast formation and bone resorption, and the increased bone resorption releases factors that enhance tumor growth (Fig 4). Bone is an abundant source of growth factors such as transforming growth factor-beta (TGFß), fibroblast growth factors, insulin-like growth factors (IGFs), platelet-derived growth factors (PDGFs), and bone morphogenic proteins. When the osteoclast resorbs bone, these factors are released and, in the case of TGFß, activated in the local bone microenvironment.24 These factors can then stimulate the growth of breast cancer cells, which in turn produce increased amounts of tumor-secreted factors that further stimulate osteoclast formation.
PTHrP is the leading candidate for an osteoclast stimulatory factor produced by breast cancer cells. PTHrP has been purified from breast cancer cells by Burtis et al5 and cloned by Suva et al.25 PTHrP binds to the PTH receptor and can cause hypercalcemia, osteoclast-mediated bone destruction, and increased renal reabsorption of calcium and excretion of phosphate. Approximately 50% of human primary breast cancers express PTHrP.26 However, more than 90% of the breast cancer metastases to bone express PTHrP. In contrast, only 70% of visceral breast cancer metastases express PTHrP. These studies suggest that the bone microenvironment enhances PTHrP production by breast cancer cells. Furthermore, Bundred et al27 have reported that PTHrP-positive breast cancers are more likely to develop bone metastases, although this is controversial.28 Guise et al29 have used the human breast cancer cell line MDA-MB-231 and an in vivo model of osteolytic metastasis to examine the role of PTHrP in breast cancer metastases. Mice injected intracardially with MDA-MB-231 cells developed osteolytic bone metastasis without hypercalcemia or increased PTHrP concentrations in their serum. However, when PTHrP concentrations were measured in bone marrow plasma from affected bones, PTHrP concentrations were increased 2.5-fold over plasma PTHrP levels. Importantly, treatment of these mice with a neutralizing monoclonal antibody to PTHrP significantly decreased the total area of the osteolytic lesions, osteoclast numbers, and the number of lesions and tumor area.29 Furthermore, TGFß production was increased in the local microenvironment of the bone metastasis. When a dominant-negative mutant of the TGFß type II receptor was transfected into the MDA-MB-231 cells, these cells were unresponsive to TGFß and, when injected intracardially into nude mice, caused less bone destruction. Transfection of the MDA-MB-231 cells with constitutively active TGFß type I receptor increased tumor production of PTHrP, enhanced osteolytic bone metastases, and decreased survival of the animals. These data support an important role for TGFß in the upregulation of PTHrP by breast cancer cells in bone and further support a role for PTHrP as the factor stimulating increased osteoclast formation and activity in breast cancer. However, PTHrP by itself cannot directly stimulate osteoclast formation in the absence of marrow stromal cells. PTHrP induces production of RANK ligand, which then stimulates osteoclast formation. Similarly, Grano et al30 demonstrated that conditioned media from MDA-231 cells increased osteoclast formation in bone marrow cultures, as well as the bone-resorbing activity of fully differentiated human osteoclasts and of osteoclast cell lines from giant cell tumors of bone. Importantly, they also showed that MDA-231 cells, although they did not produce IL-6, increased secretion of IL-6 by primary human osteoclasts and giant cell tumors of bone. These data suggest that the tumors produce factors that stimulate osteoclast formation, such as PTHrP, and induce osteoclasts to produce potent osteoclastogenic factors such as IL-6.31,32 These data suggest that IL-6 produced by osteoclasts and PTHrP produced by the tumor together can enhance osteoclast formation. This increased osteoclast formation and bone destruction then releases growth factors such as TGFß or PDGF from bone to enhance PTHrP production and tumor growth.
In addition to PTHrP, several other osteoclast stimulatory factors have been implicated as paracrine factors that stimulate osteoclast formation in breast cancer. Pederson et al33 reported that MDA-MB-231 cells also produced M-CSF, IL-1, IL-6, and TNF Other studies using mouse mammary tumor cell lines have shown that prostaglandins may play an important role in inducing osteoclast formation in breast cancer. The mouse mammary tumor (MMT) cell line, MMT060562, when cocultured with mouse marrow cells, induces osteoclast formation and bone resorption. In addition, conditioned media from cultures of MMT cells induced osteoclast formation in mouse marrow cultures. The conditioned media did not contain either PTHrP or IL-1, but it did contain high levels of PGE2. Osteoclast formation in cocultures of MMT cells with marrow was inhibited by indomethacin,34 which further supports a role for PGE2 in this process. Chikatsu et al35 have also shown that these mouse mammary cell lines can induce RANK ligand expression, which is prevented by indomethacin. Thus, PGE2 produced by the murine mammary tumor induces RANK ligand expression, which in turn stimulates osteoclast formation. Wani et al36 have shown that PGE2, in addition to enhancing RANK ligand expression by osteoblasts and marrow stromal cells, can directly enhance the effects of soluble RANK ligand on osteoclast formation.
PATHOPHYSIOLOGY OF OSTEOCLAST ACTIVATION IN MULTIPLE MYELOMA
Osteoclast-Activating Factors in Myeloma
Multiple osteoclastogenic factors have been implicated as osteoclast-activating factors (OAFs) in myeloma that may mediate the increased osteoclast activity, including TNF-beta, RANK ligand, IL-1-beta, PTHrP, hepatocyte growth factor (HGF), IL-6, TNF
IL-1ß
IL-1ß is a potent inducer of osteoclast formation and bone resorption, can induce hypercalcemia in vivo in animal models, and has been implicated as an OAF in myeloma. Freshly isolated marrow mononuclear cells from patients with myeloma produced IL-1 in their conditioned media,37,38 and the bone-resorbing activity from these cultures can be neutralized by antibodies to IL-1. Lust and Donovan39 have shown IL-1 mRNA is present in highly purified myeloma cells from patients and in a subgroup of patients with monoclonal gammopathy of unknown significance (MGUS). However, only IL-1 mRNA,40 rather than high levels of mature IL-1 protein, has been detected consistently in myeloma patients. Sati et al41 used two-color fluorescence in situ hybridization with immunofluorescence techniques and could not detect IL-1ß protein, but they did detect TNF
IL-6
IL-6 is a growth factor for myeloma cells and is present in marrow plasma samples from patients with myeloma. IL-6 can stimulate human osteoclast formation in vitro31 and in vivo32 and enhances the effects of other osteoclastogenic factors such as PTH and PTHrP.43 IL-6 mediates the effects of other inflammatory cytokines on osteoclast formation, such as IL-1 and TNF Lymphotoxin Lymphotoxin was the first OAF implicated in myeloma bone disease. Lymphotoxin is produced by normal activated lymphocytes and essentially by all myeloma cells in vitro. Garrett et al52 reported that conditioned media from myeloma cell lines stimulated osteoclastic bone resorption and that neutralizing antibodies to lymphotoxin blocked the bone-resorbing activity in this media. Furthermore, in vivo experiments demonstrated that recombinant human lymphotoxin can induce hypercalcemia in normal mice. However, myeloma cells in vivo do not seem to produce lymphotoxin, and there is no correlation between the levels of lymphotoxin and myeloma bone disease.
TNF HGF Hjertner et al55 have previously reported that myeloma cells produce HGF and that production correlated with disease activity. However, HGF was not consistently produced by all myeloma cell lines and patient samples tested. The mechanism of action of HGF seems to be induction of IL-11 secretion from human osteoblast-like cells by myeloma cells.55 IL-11 is an IL-6–like molecule that can stimulate osteoclast formation in vitro.56 However, the correlation between HGF production and bone disease in patients is not strong. RANK Ligand RANK ligand is a potent osteoclastogenic factor that, in combination with M-CSF, is sufficient to induce osteoclast formation in vitro and mediates the effects of IL-1, 1,25-(OH)2D3, PGE2, and IL-11 on osteoclast formation.57 It is unclear whether myeloma cells themselves produce RANK ligand. Although the majority of evidence suggests that RANK ligand is not produced by myeloma cells, it likely is produced by marrow stromal cells in response to myeloma cells. In a murine model of myeloma bone disease, Oyajobi et al58 have shown that RANK ligand is upregulated when murine myeloma cells come in contact with marrow stromal cells. They further showed that RANK-Fc, a soluble form of the RANK receptor that binds RANK ligand and inhibits RANK ligand activity, can decrease the bone disease in this murine model of myeloma. These data suggest that RANK ligand may be an important factor mediating the bone destruction in patients with myeloma. PTHrP As noted above, PTHrP has been identified as the mediator of the humoral hypercalcemia of malignancy, is produced by human breast cancer cell lines and prostate cancer cell lines, and induces osteoclast formation both in vivo and in vitro.59 Firkin et al60 have shown in 10 of 30 patients with hypercalcemia and myeloma that PTHrP levels are increased in the serum of these patients and that the myeloma cells produced PTHrP. Similarly, Tsujimura et al61 then reported a myeloma patient who had hypercalcemia with high serum PTHrP levels that decreased after chemotherapy. However, the majority of patients with myeloma do not have elevated PTHrP levels in their serum, nor do most myeloma cells produce PTHrP.
MIP-1
MMPs Barille et al64,65 suggested that MMPs play a critical role in bone remodeling and tumor invasion in myeloma. They showed that bone marrow stromal cells express MMP1 and MMP2, and that MMP1 and MMP2 can be regulated by cytokines produced by myeloma cells. They further showed that pro-MMP2 is activated by a soluble metalloproteinase, MMP7,65 produced by myeloma cells. MMPs can degrade bone matrix and expose bone mineral to osteoclasts for subsequent resorption.
ADHESIVE INTERACTIONS IN MYELOMA BONE DISEASE
ROLE OF OSTEOCLAST ACTIVATION IN BLASTIC METASTASES Using an animal model of osteoblastic metastasis in which MCF-7 cells overexpressing PDGF are injected intracardially in nude mice, Yi et al71 have shown that although these animals develop osteoblastic metastasis, there is an initial phase of bone resorption that is followed by extensive new bone formation. These data suggest that in this animal model of osteoblastic metastases, bone resorption precedes bone formation. In support of an important role for osteoclast activity in osteoblastic metastasis, it was recently found that bone pain in patients with metastatic prostate cancer responds to treatment with bisphosphonates, which inhibit osteoclast activity.72 When the bisphosphonate clodronate was infused intravenously at 300 mg/d into patients with prostate cancer, bone pain was relieved within 3 days, and the residual pain was usually extraosseous in origin. These data further support an important role for osteoclast activation in patients with osteoblastic metastases from prostate cancer.
In summary, several factors, including IL-1, IL-6, PTHrP, RANK ligand, and MIP-1
Supported by research funds from the Veterans Administration and by National Institutes of Health grant nos. AG13625, AR44603, and DE12603.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
