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.
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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)