ReviewTumor necrosis factor-α: molecular and cellular mechanisms in skeletal pathology
Introduction
Seventeen years have passed since the identification and cloning of tumor necrosis factor-α (TNF) by Beutler et al. (1985). Since then, numerous studies established TNF as a major mediator of inflammation, delineated its intracellular signaling pathways, and identified target genes that implement its function (for reviews, see Beutler, 1999, Wajant et al., 1999, Screaton and Xu, 2000, MacEwan, 2002). The role of TNF as a participant in the inflammatory process should be viewed in three ways. The first is as a stimulus of acute inflammation as in classic models of sepsis and precipitous immune responses. The second is as a chronic contributor to autoimmune disorders such as rheumatoid arthritis, Crohn's disease, and psoriatic arthritis. A third, more recent view, is that TNF may act in an indolent and insidious manner as a low-grade stimulus after menopause (estrogen deficiency), in obesity, and with aging. It is the third modus operandi that is suggested to contribute to the pathophysiology of osteoporosis, insulin resistance, and atherogenesis (Bruunsgaard et al., 2001). Substantial in vitro and in vivo evidence suggests that TNF has a central role in the pathophysiology of skeletal loss following menopause Pacifici, 1996, Horowitz et al., 2001. TNF gained importance as a local regulator of bone cell function for good reason. Data derived from early work identified TNF as a skeletal catabolic agent. TNF treatment of cultured bone explants or cell cultures of mineralizing osteoblasts caused increased calcium release and suppression of matrix protein production, suggesting stimulation of bone resorption and inhibition of formation Bertolini et al., 1986, Canalis, 1987, Smith et al., 1987, Stashenko et al., 1987, Centrella et al., 1988, Gowen et al., 1988, Nanes et al., 1989, Li and Stashenko, 1992. These in vitro results were extended to animal models in the context of ectopic bone formation, estrogen deficiency-induced bone loss, and in models of periarticular bone destruction in the inflamed joint. Here, increased production of TNF was demonstrated as part of the overall cytokine stimulus, and blockade of TNF action was shown to alleviate bone loss Pacifici et al., 1991, Kitazawa et al., 1994, Kimble et al., 1995, Kimble et al., 1996, Kimble et al., 1997, Cenci et al., 2000, Chabaud and Miossec, 2001.
This review will focus on the cellular and molecular mechanism of TNF action in the pathophysiology of osteoporosis. Although TNF is just one of several cytokines that participate in this process, evidence suggests that TNF performs a central role.
Section snippets
Sources of TNF
A major focus of osteoporosis research has been to understand the reasons for accelerated bone resorption following menopause; thus, an obvious question has been how estrogen deficiency leads to increased osteoclast activity and ultimately osteoporosis. Early work by McSheehy et al. and Thomson et al. showed that conditioned media derived from osteoblasts that were stimulated with either parathyroid hormone (PTH), vitamin D, TNF, or interleukin-1 (IL-1) increased osteoclastogenesis McSheehy and
TNF signal pathways in skeletal cells
A trimeric form of TNF binds one of two cell surface receptors, TNFR1 (TNFRSF1A, p55) and TNFR2 (TNFRSF1B, p75) to initiate a signal cascade that causes inflammatory gene activation, selective gene repression, and for the TNFR1, an apoptotic response (Fig. 1). From receptor to gene, numerous signal pathways provide an opportunity for divergence of the skeletal response. As will be discussed below, the TNF signal pathways include features linked to the specificity of the stimulation of bone
Mechanisms of estrogen inhibition of TNF
The inhibitory effect of estrogen on TNF production and its relationship to osteoporosis was described above. Two mechanisms have been considered to account for estrogen inhibition of TNF production. In the first, estrogen directly suppresses transcription of the TNF gene, as proposed by Srivastava et al. (1999). In this study using RAW 264.7 cells (which can be stimulated to acquire the osteoclast phenotype), estrogen decreased transcriptional activity of the TNF promoter. Mutation of an AP-1
Effect of TNF on osteoclasts: the relationship between TNF and RANKL in osteoclastogenesis
Osteoclasts are derived from myeloid progenitors of the monocyte macrophage lineage, as shown in Fig. 2. The role of TNF as a stimulator of osteoclastogenesis has been confirmed by numerous investigators Manolagas, 1995, Pacifici, 1996, Kudo et al., 2002. As discussed above, the effect of TNF may be indirect via osteoblast signals, but may also be direct Komine et al., 2001, Kudo et al., 2002. The expression of a number of transcription factors, including the prototypical p65/p50 Nf-κB, is
Effect of TNF on osteoblasts
The maintenance of a healthy skeleton requires a balance of bone resorption and formation rates. To achieve this, bone formation by osteoblasts must increase in response to the resorptive stimulus of TNF; however, this does not occur. TNF assails bone by stimulating resorption while simultaneously inhibiting the expected homeostatic response of new bone formation. TNF impairs the function of bone-forming osteoblasts in three ways: (1) by suppressing mature osteoblast function such as the
Conclusion
Although many factors contribute to the pathophysiology of bone loss, TNF has an important and central role. A normally coupled resorption/formation system important for the homeostasis of bone is disturbed in the presence of elevated TNF, whether acute, as in a flare of inflammatory arthritis, or insidious with estrogen loss and aging. Increased production of TNF, particularly in postmenopausal women, damages bone by increasing bone resorption while simultaneously inhibiting bone-forming
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