Genetic influences on the circulating cytokines involved in osteoclastogenesis

he tumour necrosis factor family molecule RANKL (receptor activator of nuclear factor-kB ligand), its cellular receptor RANK, and the decoy receptor, osteoprotegerin (OPG) represent a novel cytokine triad with pleiotropic effects on bone metabolism, the immune system, and endocrine functions. 1As illustrated in figure 1, RANKL is expressed on the osteoblast/stromal cell surface, binds to its receptor-RANK on the surface of haematopoietic precursor cells and, in the presence of macrophage colony stimulating factor (M-CSF), stimulates differentiation, fusion, activation, and survival of osteoclasts. 2 3These four molecules, acting in accord, are the major regulators of osteoclast formation and function.It has been claimed that binding M-CSF and RANKL to their respective receptors is the necessary and sufficient condition to initiate osteoclastogenesis. 4On the other hand, RANKL is abundantly produced by activated T lymphocytes, and it prevents apoptosis and prolongs survival of dendritic cells, which also express large amounts of the receptor for RANKL (fig 1).This dual function of the RANKL/ RANK/OPG system explains why autoimmune diseases, cancers, leukemias, asthma, chronic viral infections, and periodontal disease result in systemic and local bone loss.Numerous reports now implicate the altered RANKL/ RANK/OPG system physiology as a factor in the development and severity of many diseases.Three such maladies for which a growing volume of literature exists are rheumatoid arthritis, osteoporosis, and skeletal metastases.Neoplastic cells in giant cell tumours 5 and multiple myeloma 6 express RANKL as well as other osteolytic factors, and the OPG/ RANKL ratio was significantly lower in patients with these osteolytic tumours than in those with non-lytic neoplasms. 7-9However, patients with some lytic solid tumours, including advanced prostate cancer 10 and Hodgkin's disease, 8 have higher serum OPG concentrations than do healthy individuals, with the levels often more elevated in subjects with metastatic rather than localised disease. 10It has been shown that compared with healthy subjects or patients with other types of tumour, patients with myeloma bone disease have lower OPG levels in their serum (or within the bone microenvironment), and that these low OPG serum levels are inversely correlated with the severity of the disease.One study even suggests that serum levels of OPG could serve as a cardiovascular risk factor. 11Further support for OPG being a vascular regulator comes from an epidemiological study conducted by Browner and colleagues, 12 wherein the serum OPG was 30% higher in women with diabetes than in nondiabetic women, and was also associated with increased cardiovascular mortality.By studying well characterised patient cohorts with endocrine and immune diseases such as Cushing's syndrome, acromegaly, growth hormone deficiency, HIV infection, and common variable immunodeficiency (CVI), the investigators reported significantly increased OPG serum levels in both groups with persistent immune activation (HIV, CVI). 13All these data provide further evidence that the immune system