Cytokines and osteoporosis

Abstract

Cytokines are polypeptide molecules which modulate the biologic actions of cells. They are recognized as local factors that regulate the various functions of bone cells and are implicated in various metabolic bone diseases including osteoporosis. Several interleukins (ILs) appear to be key players: IL-1 has potent bone-resorbing activities both in vitro and in vivo . It stimulates osteoclast formation which may depend on prostaglandins. In vivo , IL-1 produces high bone turnover with bone volume loss and hypercalcemia. The role of IL-1 in postmenopausal osteoporosis is unclear since current evidence provides conflicting results. IL-4 inhibits bone resorption in vitro whereas an in vivo study in transgenic mice reveals low turnover osteoporosis. IL-6 is another major cytokine which has been extensively studied in bone diseases especially estrogen-deficient osteoporosis. IL-6 is believed to induce bone resorption by activating osteoclastic stem cells rather than mature osteoclasts although the exact mechanism and its role in osteoporosis need to be clarified. IL-11 has been shown to enhance bone resorption and inhibit bone formation in vitro , however, its significance in bone metabolism in vivo is as yet undefined. Tumor necrosis factor (TNF), like IL-1, is a bone resorber both in vitro and in vivo and is one of the cytokines that may well play an important role in postmenopausal osteoporosis. Lymphotoxin (LT), similar to TNF, stimulates bone resorption in vitro but its role in osteoporosis has not been established. The effects of several colony-stimulating factors (CSFs) have also been investigated. Despite no bone-resorbing activity, granulocyte-CSF (G-CSF) is able to produce osteoporosis in transgenic mice and monocyte-CSF (M-CSF) administration is capable of correcting murine osteopetrosis. Interferon gamma (IFNγ) has been recognized as an inhibitor of bone resorption in vitro until recently when in vivo studies demonstrated its bone-resorbing effect by producing loss of bone volume in rats and in osteopetrotic patients. As another bone resorber in vitro , leukemia inhibitory factor (LIF) is also a candidate in the pathogenesis of osteoporosis although further studies are needed. The problem of defining roles for these cytokines may rest in the different biological systems, that is, in vitro versus in vivo studies, and interaction of systemic hormones and a stepwise cascade series of regulatory events that make one particular cytokine's role difficult to evaluate in isolation.