Mechanism of bone metastasis: The role of osteoprotegerin and of the host-tissue microenvironment-related survival factors
Introduction
Osteoprotegerin (OPG), also known as osteoclastogenesis inhibitory factor (OCIF), TNF receptor-related molecule 1 (TR-1) and follicular dentodritic cell receptor molecule 1 (FDCR-1), is a cytokine and a member of the tumor necrosis factor (TNF) receptor syperfamily [1]. The human OPG gene is located at chromosome 8q23-24 and contains five different exons spread over a total of 29 kb [1]. It is a glycoprotein comprising 401 amino acid residues arranged into seven structural domains, which is found as either a 60 kDa monomer or 120 kDa dimmer linked by disulfide bonds [2], [3]. It is the dimeric form of the protein that has the highest heparin-binding capacity and also the highest hypocalcaemic ability [1]. In contrast to all other TNF receptor family members, OPG, a RANKL (receptor activator of nuclear factor-kB ligand) homolog, lacks transmembrane and cytoplasmic domains and is considered as a soluble protein and more specifically a soluble, decoy receptor for RANKL [2], [3]. The N-terminal region contains four domains (D1–D4) that are rich in cysteine. The C-terminal region contains not only two death domain homologous regions (D5 and D6) but also a region (D7) with a heparin-binding site and a cysteine residue necessary for homodimerization [3]. OPG mRNA is expressed in numerous tissues, such as lung, heart, kidney, prostate, testis, liver, stomach, intestine, brain, spinal cord, thyroid gland and bone [3]. However, OPG is produced by osteoblast and stromal cells.
RANKL is a member of TNF family and also known as osteoprotegerin ligand (OPG-L), osteoclast differentiation factor (ODF), or TNF related activation – induced cytokine (TRANCE) [4]. It is produced by osteoblasts, cells of bone stroma and by activated T lymphocytes [5]. RANKL, just as OPG, is crucial for differentiation and osteoresorption function of the osteoclast. Mice deficient in RANKL have extensive osteopetrosis due to a lack of functional osteoclasts [5]. Furthermore, it is a critical factor not only in the bone remodeling process but also for the immune system, as it regulates the development of lymph nodes and Peyer’s patches, serves as an important molecule in optimal T cell activation and mediates dendritic cell survival [2], [6]. So it contributes importantly to the inflammation [6].
The downstream signaling receptor for RANKL is RANK, which is a crucial protein for all calciumtropic hormones and proresorptive cytokines to increase calcaemia and multiplication of osteoclasts in the bone [6], [7]. It can be found in the membrane of cells of osteoclast line and in dendritic cells. RANK is considered as a hematopoietic surface receptor that controls osteoclastogenesis and calcium metabolism [5], [6], [7].
Concerning the control of bone remodeling by the OPG–RANKL–RANK system, RANKL is a potent inducer of osteoclast formation [8]. Osteotropic factors—1,25-dihydroxyvitamin D3, parathyroid hormone, prostaglandin E2, and interleukin 11—induce the formation of osteoclasts by up-regulating RANKL expression on the surface of marrow stromal cells and immature osteoblasts. RANKL binds to its receptor, RANK, on the surface of osteoclast precursors and signals to induce osteoclast formation and to promote osteoclast survival. By binding to RANKL on osteoblast-stromal cells OPG blocks the RANK–RANKL interaction between osteoblast–stromal cells and osteoclast precursors. This interaction inhibits the differentiation of the osteoclast precursor into a mature osteoclast [8]. Human OPG specifically acts on bone, increasing bone density and bone volume [2], while animal OPG acts as a critical regulator of postnatal bone mass [9]. It is also known that human OPG prevents osteoclastogenesis and bone destruction [7]. OPG knockout mice have severe osteoporosis with near total loss of cancellous bone [1]. Consequently, differentiation, activation and survival of osteoclasts are regulated, by the balance between OPG and RANK ligand (RANKL).
Section snippets
The role of other regulating factors in bone formation and resorption
New bone formation and bone resorption are complex procedures; the balance between them depends on many factors, for example Ca2+ and P concentrations, 1,25(OH)2-vitD3, and parathormon (PTH) [10], [11], [12]. Many other molecules are thought to participate in the pathophysiology of osteolytic and osteoblastic bone metastases as well.
General mechanisms of bone metastasis
In patients with cancer, metastasis represents a major cause of morbidity and mortality. Following liver and lungs, bone is the third most frequent site of hematogenous tumor metastasis in the human body [24], [25], [26], indicating that the bone microenvironment provides the necessary conditions for the growth of many human tumors [24]. Breast and prostate carcinomas have a great avidity for bone [24], because the molecular interactions between these cancer cells and host cells favor the
The role of bone microenvironment
Simultaneously to the investigations of the mechanisms responsible for bone metastasis, it has been very important to determinate why some cancers have such a high avidity for bone. One reason might be the high vascularity of bone and bone marrow. However, there are other highly vascularized organs, to which some cancers seldom metastaze. Perhaps it is the bone microenvironment that provides cancer cells with the ability to survive and proliferate in the bone.
In the case of bone metastasis, we
Prostate cancer metastases to bone
Prostate cancer, the most frequent cancer in men, gives very usually metastasis to bone, as more than 84% of patients demonstrate skeletal lesions [24], [33], [34]. Although such metastases have been traditionally characterized as osteoblastic, today it is well known that both bone formation and resorption are dysregulated and participate in the metastatic lesions [32]. Therefore, it is interesting to investigate the role of OPG in prostate cancer, as its overexpression by tumor cells could
The role of OPG in other cancers
The multiple role of OPG in prostate and breast cancer, its ability to promote the survival and proliferation of cancer cells and its possible correlation with tumor grade and stage have lead to further investigations of the role of OPG in other cancers leading to useful conclusions about the pathophysiology of these tumors. Studies have been carried out, not only in cancers with avidity to the skeleton, but also in tumors that do not usually give osseous metastases.
Therapeutic approaches
Preventing a bone lesion from developing and limiting the progression of an established bone metastasis should be the primary goals of treating metastatic bone disease. However, the currently available therapies for bone metastasis such as bisphosphonates, radiotherapy, radiopharmaceuticals and surgery focus only on symptomatic management [8], [58]. Concerning bisphosphonates, it should be mentioned that they block not only bone resorption but also tumor-cell mitosis and stimulate tumor-cell
Conclusion
As metastasis is the only most catastrophic complication of cancer, understanding the biology of the process of metastasis should provide greater insights into normal cell behavior as well as lead to new therapies that limit or prevent this cause of mortality in patients with cancer. Concerning the role of several factors, including OPG in bone metastasis, there has been little detailed examination of the factors that may be responsible for osteolysis and osteoblastic process in tumors other
Conflicts of interest
I, Bernhard Schaller, declare on behalf of all authors that none of the authors has any proprietary, financial, professional or other personal interest of any nature or kind in any product, service and/or company that could be constructed as influencing the position presented in, or the review of, the manuscript entitled, “Mechanisms of bone metastasis: The role of osteoprotegerin and of the host-tissue microenvironment-related survival factors”
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