Bone and Cytokines: Beyond IL-1, IL-6 and TNF-α

A relationship between the immune system and bone resorption was essentially recognized nearly 25 years ago with the first description of a factor, released from phytohemagglutinin-stimulated human leukocytes, that induced bone resorption in vitro. This factor, designated in 1974 [1] as osteoclast activating factor (OAF), has been assigned to many products secreted by cells of the immune system. But what was OAF and did a cell of the immune system secrete this factor or did a lymphokine induce OAF from another cell type in the bone environment? This has been a perplexing problem since that first description of an immune cell factor(s) that induces bone resorption, but has the nature of this factor(s) been discovered as yet? Or is OAF a family of cytokines working in concert to induce osteoclast progenitor cell differentiation and activation? It has become very clear since the first description of OAF that several factors produced by cells of the immune system affect osteoclast formation and function in vitro. The most widely studied factors are interleukin-1, interleukin-6, and tumor necrosis factor-a. Although the interleukins (literal meaning, between leukocytes) were initially described as products of lymphocytes that affected other lymphocytes and tissue cells [2], it has become clear that these cytokines are synthesized and released by a variety of cell types inhabiting bone including bone marrow stromal cells [3–5] and osteoblasts [5–10]. These three lymphokines, individually or as a group, have been found to affect osteoclastogenesis indirectly, via induction of OAF from osteoblasts [11–14]. As a result of mounting in vitro evidence, studies were undertaken to examine the relationship of these three cytokines to the osteopenia associated with metabolic bone disease in humans, such as postmenopausal osteoporosis and hypercalcemia of malignancy. IL-1 was the first of these cytokines to be linked to the accelerated bone resorption seen in idiopathic [15] and postmenopausal osteoporosis [16, 17]. TNF-a has been shown to be involved in tumor-induced bone resorption [18, 19] and nontumor-induced osteopenia [12, 20–22] and along with IL-1, is secreted in higher amounts from mononuclear cells of postmenopausal women than premenopausal women [23, 24]. IL-6, a member of the gp130 signal transduction family which includes IL-11, oncostatin M, and leukemia inhibitory factor (LIF) [25–27], induces osteoclastogenesis that ensues when mice are ovariectomized (OVX) [28–30] and is also found to be secreted in higher levels from mononuclear cells isolated from postmenopausal women [24]. These three cytokines have been described as inducing osteoclastogenesis either by inducing the proliferation of osteoclast precursor cells or inducing the activation of the differentiated osteoclast [22, 26, 28, 31–36]. And recently, bone loss has been prevented in OVX rats treated with the IL-1 and TNF-a inhibitors, IL-1 receptor antagonist and TNF binding protein, respectively, suggesting that IL-1 and TNF-a regulate postmenopausal bone resorption [37]. Although it is now apparent that IL-1 and TNF-a play major roles in the process of bone resorption in many metabolic bone diseases, the accumulated data suggest that they act in an upstream capacity to induce downstream cytokines such as IL-6, IL-8, IL-11, GM-CSF, and CSF-1 which have more direct roles in the process of osteoclast development, activation, and differentiation. But how these products of lymphocytes, and nonlymphocytic cells, are induced subsequent to estrogen withdrawal and how they regulate the process of osteoclast formation, differentiation, and activation are still key questions that have no answers at the present time. In fact, a controversy remains as to the role of IL-1, TNF-a, and IL-6 in the process of postmenopausal osteoporosis in the human [23, 24, 37–42]. Very few studies have compared the expression of these cytokines with localized and general osteopenia that occurs in inflammatory diseases such as autoimmune diseases and posttransplantation osteopenia. Thus, new evidence is now taking us beyond IL-1, IL-6, and TNF-a with respect to osteoclastogenesis and the process of bone resorption.