Syk, c-Src, the αvβ3 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption

Zou, Wei; Kitaura, Hideki; Reeve, Jennifer; Long, Fanxin; Tybulewicz, Victor L. J.; Shattil, Sanford J.; Ginsberg, Mark H.; Ross, F. Patrick; Teitelbaum, Steven L.

doi:10.1084/jem2043oia8

Cited by 19 publications

(41 citation statements)

References 9 publications

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“…Because the strong inhibition of osteoclastogenesis and NFATc1 expression by IL‐27 could not be explained solely by its inhibition of RANK expression, we investigated the effects of IL‐27 on other pathways implicated in the induction of NFATc1 expression. The immunoreceptors TREM‐2, osteoclast‐associated receptor (OSCAR), signal‐regulatory protein β1 (SIRPβ1), and immunoglobulin‐like transcript 7 (ILT‐7; homolog of murine paired immunoglobulin‐like receptor A) and the integrin αvβ3 provide signaling via the ITAM‐containing adaptor proteins DNAX‐activating protein of 12 kd (DAP‐12) and Fc receptor γ (FcRγ) and cooperate with RANK signaling pathways to induce NFATc1 expression and osteoclastogenesis (29–32). We therefore investigated the effects of IL‐27 on the expression of these costimulatory receptors and DAP‐12/FcRγ.…”

Section: Resultsmentioning

confidence: 99%

“…The driving force of this commitment‐differentiation process is the interaction of RANKL (a cytokine member of the tumor necrosis factor superfamily) with its receptor, RANK, which is expressed on the surface of osteoclast precursors (27, 28). Effective osteoclastogenesis requires costimulatory calcium‐mediated signals from immunoreceptor tyrosine–based activation motif (ITAM)–coupled receptors that cooperate with RANK signaling to induce expression of nuclear factor of activated T cells c1 (NFATc1) and the downstream osteoclast differentiation program (29–32). In humans, triggering receptor expressed on myeloid cells 2 (TREM‐2) is a key costimulatory receptor, since loss‐of‐function mutations in TREM‐2 compromise bone remodeling and lead to the development of Nasu‐Hakola disease (also called polycystic lipomembranous osteodysplasia with sclerosing leukoengephalopathy) (33, 34).…”

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confidence: 99%

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Interleukin‐27 inhibits human osteoclastogenesis by abrogating RANKL‐mediated induction of nuclear factor of activated T cells c1 and suppressing proximal RANK signaling

Kalliolias¹,

Zhao²,

Triantafyllopoulou³

et al. 2010

Arthritis & Rheumatism

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Objective. Interleukin-27 (IL-27) has stimulatory and regulatory immune functions and is expressed in rheumatoid arthritis (RA) synovium. This study was undertaken to investigate the effects of IL-27 on human osteoclastogenesis, to determine whether IL-27 can stimulate or attenuate the osteoclast-mediated bone resorption that is a hallmark of RA.Methods. Osteoclasts were generated from bloodderived human CD14؉ cells. The effects of IL-27 on osteoclast formation were evaluated by counting the number of tartrate-resistant acid phosphatase-positive multinucleated cells and measuring the expression of osteoclast-related genes. The induction of nuclear factor of activated T cells c1 (NFATc1) and the activation of signaling pathways downstream of RANK were measured by immunoblotting. The expression of key molecules implicated in osteoclastogenesis (NFATc1, RANK, costimulatory receptors, and immunoreceptor tyrosinebased activation motif-harboring adaptor proteins) was measured by real-time reverse transcriptionpolymerase chain reaction. Murine osteoclast precursors obtained from mouse bone marrow and synovial fluid macrophages derived from RA patients were also tested for their responsiveness to IL-27.Results. IL-27 inhibited human osteoclastogenesis, suppressed the induction of NFATc1, downregulated the expression of RANK and triggering receptor expressed on myeloid cells 2 (TREM-2), and inhibited RANKL-mediated activation of ERK, p38, and NF-B in osteoclast precursors. Synovial fluid macrophages from RA patients were refractory to the effects of IL-27. In contrast to the findings in humans, IL-27 only moderately suppressed murine osteoclastogenesis, and this was likely attributable to low expression of the IL-27 receptor subunit WSX-1 on murine osteoclast precursors.Conclusion. IL-27 inhibits human osteoclastogenesis by a direct mechanism that suppresses the responses of osteoclast precursors to RANKL. These findings suggest that, in addition to its well-known antiinflammatory effects, IL-27 plays a homeostatic role in restraining bone erosion. This homeostatic function is compromised under conditions of chronic inflammation such as in RA synovitis.Interleukin-27 (IL-27) is a member of the IL-12 family of heterodimeric cytokines that also includes . IL-27 comprises the Epstein-Barr virus-induced protein 3 and p28 subunits, which share similarity with the p40 and p35 subunits of IL-12, respectively (4). The IL-27 receptor is a heterodimer composed of a WSX-1 subunit (also termed T cell cytokine receptor), which confers ligand specificity, and the gp130 signaling subunit, which is also utilized by the IL-6 family of cytokines (5). IL-27 activates the JAK/STAT signal transduction pathway in a contextdependent manner, since its effects vary depending on Dr.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Interleukin‐27 inhibits human osteoclastogenesis by abrogating RANKL‐mediated induction of nuclear factor of activated T cells c1 and suppressing proximal RANK signaling

Kalliolias¹,

Zhao²,

Triantafyllopoulou³

et al. 2010

Arthritis & Rheumatism

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“…Although the precise extracellular molecules inducing osteoclast polarization are incompletely understood, they are likely mediated via the αvβ3 integrin (28,29). Integrins are α/β transmembrane heterodimers existing in a basal (low binding affinity) or an activated (high binding affinity) state.…”

Section: Osteoclast Polarization and The Cytoskeletonmentioning

confidence: 99%

“…We find that c-Src, in its inactive state, constitutively associates with the β3 cytoplasmic domain of the unliganded integrin. αvβ3 activation recruits Syk, another tyrosine kinase, to the β3 tail, where it is phosphorylated by the now active c-Src (28). Recruitment and activation of Syk depends upon its association with the ITAM proteins DAP12 and FcRγ (28).…”

Section: Gef: Guanine Nucleotide Exchange Factormentioning

confidence: 99%

“…Confirming Vav3's participation in the αvβ3/Rac signaling pathway, occupancy of the integrin fails to activate Rac in the absence of this GEF. Syk, following recruitment to the activated αvβ3/c-Src complex, acts as the Vav3 kinase (Figure 4) (28). Phosphorylated Vav3 activates Rac, leading in turn to the organization of the osteoclast cytoskeleton.…”

Section: Gef: Guanine Nucleotide Exchange Factormentioning

confidence: 99%

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The Osteoclast: Friend or Foe?

Novack

Teitelbaum

2008

Annu. Rev. Pathol. Mech. Dis.

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341

283

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Bone is a dynamic organ constantly remodeled to support calcium homeostasis and structural needs. The osteoclast is the cell responsible for removing both the organic and inorganic components of bone. It is derived from hematopoietic progenitors in the macrophage lineage and differentiates in response to the tumor necrosis factor family cytokine receptor activator of NF kappa B ligand. alpha v beta 3 integrin mediates cell adhesion necessary for polarization and formation of an isolated, acidified resorptive microenvironment. Defects in osteoclast function, whether genetic or iatrogenic, may increase bone mass but lead to poor bone quality and a high fracture risk. Pathological stimulation of osteoclast formation and resorption occurs in postmenopausal osteoporosis, inflammatory arthritis, and metastasis of tumors to bone. In these diseases, osteoclast activity causes bone loss that leads to pain, deformity, and fracture. Thus, osteoclasts are critical for normal bone function, but their activity must be controlled.

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Glucocorticoid excess in mice results in early activation of osteoclastogenesis and adipogenesis and prolonged suppression of osteogenesis: A longitudinal study of gene expression in bone tissue from glucocorticoid‐treated mice

Yao¹,

Cheng²,

Busse³

et al. 2008

Arthritis & Rheumatism

219

181

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Objective. Glucocorticoid (GC) excess induces alterations in bone metabolism that weaken bone structure and increase fracture risk. The aim of this study was to identify genes associated with bone metabolism in GC-treated mice, by performing a microarray analysis.Methods. Long bones from mice exposed to GC excess were collected after 0, 7, 28, and 56 days of treatment, to measure bone microarchitecture and extract RNA for microarray analyses.Results. Bone loss in this animal model was confirmed by changes in bone turnover markers as well as bone architecture, as measured by microfocal computed tomography. GC excess induced an early upregulation of genes involved in osteoclast activation, function, and adipogenesis, which peaked on day 7. The expression of genes associated with osteoclast cytoskeletal reorganization and genes associated with matrix degradation peaked on day 28. On day 28 and day 56, the expression of genes associated with osteoblast activation and maturation was decreased from baseline, while the expression of Wnt antagonists was increased. In addition, the expression of genes expressed in osteocytes associated with bone mineralization was significantly higher at the later time points, day 28 and day 56. Reverse transcription-polymerase chain reaction confirmed the results of microarray analysis in selected genes.Conclusion. GC excess is associated with early activation of genes associated with osteoclastogenesis and adipogenesis and a later suppression of genes associated with osteogenesis and mineralization. Novel interventions with agents that modulate either Wnt signaling or mineralization may be effective in GCinduced osteoporosis.Glucocorticoids (GCs) are frequently prescribed for the treatment of many chronic noninfectious inflammatory disorders, including arthritis, pulmonary diseases, and skin diseases. Although GCs are potent antiinflammatory agents, long-term use results in several adverse side effects, the most common of which is bone loss, which increases the risk of fracture throughout the skeleton (1). Patients treated with GCs have been reported to have an early, rapid increase in bone resorption accompanied by a prolonged reduction in bone formation (2).The influence of GCs on bone resorption was thought to be indirect and related in part to reduced calcium absorption and increased renal calcium excretion (3). However, recent studies have shown that GCs act directly on osteoclasts to decrease apoptosis of

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Syk, c-Src, the αvβ3 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption

Cited by 19 publications

References 9 publications

Interleukin‐27 inhibits human osteoclastogenesis by abrogating RANKL‐mediated induction of nuclear factor of activated T cells c1 and suppressing proximal RANK signaling

Interleukin‐27 inhibits human osteoclastogenesis by abrogating RANKL‐mediated induction of nuclear factor of activated T cells c1 and suppressing proximal RANK signaling

The Osteoclast: Friend or Foe?

Glucocorticoid excess in mice results in early activation of osteoclastogenesis and adipogenesis and prolonged suppression of osteogenesis: A longitudinal study of gene expression in bone tissue from glucocorticoid‐treated mice

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