Negative regulation of osteoclastogenesis and bone resorption by cytokines and transcriptional repressors

Arthritis Research & Therapy, Jul 2011

Bone remodeling in physiological and pathological conditions represents a balance between bone resorption mediated by osteoclasts and bone formation by osteoblasts. Bone resorption is tightly and dynamically regulated by multiple mediators, including cytokines that act directly on osteoclasts and their precursors, or indirectly by modulating osteoblast lineage cells that in turn regulate osteoclast differentiation. The critical role of cytokines in inducing and promoting osteoclast differentiation, function and survival is covered by the accompanying review by Zwerina and colleagues. Recently, it has become clear that negative regulation of osteoclastogenesis and bone resorption by inflammatory factors and cytokines, downstream signaling pathways, and a newly described network of transcriptional repressors plays a key role in bone homeostasis by fine tuning bone remodeling and restraining excessive bone resorption in inflammatory settings. In this review we discuss negative regulators of osteoclastogenesis and mechanisms by which these factors suppress bone resorption.

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Negative regulation of osteoclastogenesis and bone resorption by cytokines and transcriptional repressors

Baohong Zhao 0 Lionel B Ivashkiv 0 1 0 Arthritis and Tissue Degeneration Program, Hospital for Special Surgery , New York, NY 10021 , USA 1 Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Science , New York, NY 10021 , USA Bone remodeling in physiological and pathological conditions represents a balance between bone resorption mediated by osteoclasts and bone formation by osteoblasts. Bone resorption is tightly and dynamically regulated by multiple mediators, including cytokines that act directly on osteoclasts and their precursors, or indirectly by modulating osteoblast lineage cells that in turn regulate osteoclast differentiation. The critical role of cytokines in inducing and promoting osteoclast differentiation, function and survival is covered by the accompanying review by Zwerina and colleagues. Recently, it has become clear that negative regulation of osteoclastogenesis and bone resorption by inflammatory factors and cytokines, downstream signaling pathways, and a newly described network of transcriptional repressors plays a key role in bone homeostasis by fine tuning bone remodeling and restraining excessive bone resorption in inflammatory settings. In this review we discuss negative regulators of osteoclastogenesis and mechanisms by which these factors suppress bone resorption. - Introduction Osteoclasts, the exclusive bone resorptive cells, play an important role not only in physiological bone development and remodeling, but also function actively as a central pathogenic factor (culprit) leading to musculoskeletal tissue damage and accelerating pathogenesis of diseases characterized by inflammatory osteolysis, including rheumatoid arthritis, psoriatic arthritis, periodontitis and peri-prosthetic loosening. In these diseases, abnormally enhanced osteoclast formation and activity cause bone loss that can result in pain, deformity, osteopenia, osteoporosis and even fracture. It has been extensively documented that a variety of inflammatory molecules, such as TNF-, IL-1, IL-17, and Toll-like receptor (TLR) ligands, promote osteoclastogenesis synergistically with RANKL (Receptor activator of NF-B ligand) to induce pathological bone resorption in inflammatory settings. In addition, there is a great deal of recent evidence that various inflammatory factors produced by activated immune cells act as antiosteoclastogenic factors by different mechanisms (Figure 1). Suppression of osteoclastogenesis by inflammatory factors and cytokines functions as a feedback inhibition system that limits bone resorption and tissue damage associated with infection or inflammation. These inflammatory factors can suppress osteoclastogenesis directly by inhibiting differentiation of osteoclast precursors or indirectly by regulating differentiation and expression of RANKL and osteoprotegerin (OPG) by mesenchymal cells, such as osteoblastic/stromal cells and synovial fibroblasts, or by T cells. Osteoclast differentiation is physiologically triggered by RANKL in the presence of macrophage colonystimulating factor (M-CSF) and unknown co-stimulatory factors. Upon RANK stimulation, a broad range of signaling cascades are activated, such as canonical and noncanonical NF-B pathways, protein tyrosine kinases, such as BtK/Tec, calcium signaling, and mitogen-activated protein kinase (MAPK) pathways, including p38 and Erk. These signaling cascades, which are reviewed in depth in the accompanying review by Zwerina and colleagues [1], lead to induction of the transcription factor NFATc1 (Nuclear factor of activated T cells, cytoplasmic 1), which serves as a master regulator of osteoclastogenesis, together with other transcription factors, such as NF-B and c-fos, to drive osteoclastogenesis [2] (Figure 2). More recently, transcriptional repressors that suppress RANKLinduced gene expression and differentiation have been described (Figure 2). These repressors can work as homeostatic factors in regulating osteoclastogenesis in physiological bone development and remodeling, and also as feedback inhibitors that limit bone resorption associated with inflammation. The extent of bone destruction in inflammatory diseases is determined by the balance between osteoclastogenic and anti-osteoclastogenic factors. Cytokines IL-4/IL-13 and granulocyte-macrophage colonystimulating factor IL-4 and IL-13 have pleiotropic immune functions and are produced by Th2 lymphocytes, although IL-13 can also be produced by stromal cells. Since IL-4 and IL-13 utilize closely related receptor complexes, they have many overlapping features, including downstream signaling and some biological functions. IL-4, more effectively than IL-13, directly prevents osteoclast precursors from differentiating into osteoclasts in a signal transducer and activator of transcription (STAT)6-dependent manner [3,4]. IL-4 suppresses RANK expression, NF-B, MAPK and calcium signaling, and expression of NFATc1 and cFos during osteoclastoge (...truncated)


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Baohong Zhao, Lionel B Ivashkiv. Negative regulation of osteoclastogenesis and bone resorption by cytokines and transcriptional repressors, Arthritis Research & Therapy, 2011, pp. 234, 13, DOI: 10.1186/ar3379