MCP-1-induced Human Osteoclast-like Cells Are Tartrate-resistant Acid Phosphatase, NFATc1, and Calcitonin Receptor-positive but Require Receptor Activator of NFκB Ligand for Bone Resorption

Kim, Michael S.; Day, Christopher J.; Selinger, Christina; Magno, Carly; Stephens, Sebastien J. R.; Morrison, Nigel Alexander

doi:10.1074/jbc.m510156200

Cited by 132 publications

(117 citation statements)

References 28 publications

(46 reference statements)

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“…In addition, osteoclast progenitors produce a number of cytokines, including chemokines (28). Although chemokine receptor signaling alone is not sufficient for formation of functional osteoclast, chemokines have a costimulatory effect on RANKL-stimulated osteoclastogenesis (29).…”

Section: Discussionmentioning

confidence: 99%

Important roles of PI3Kγ in osteoclastogenesis and bone homeostasis

Kang

Chang

Hurley

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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G protein-coupled receptor-regulated PI3Kγ is abundantly expressed in myeloid cells and has been implicated as a promising drug target to treat various inflammatory diseases. However, its role in bone homeostasis has not been investigated, despite the fact that osteoclasts are derived from myeloid lineage. We therefore carried out thorough bone phenotypic characterization of a PI3Kγ-deficient mouse line and found that PI3Kγ-deficient mice had high bone mass. Our analyses further revealed that PI3Kγ deficiency did not affect bone formation because no significant changes in osteoblast number and bone formation rate were observed. Instead, the lack of PI3Kγ was associated with decreased bone resorption, as evidenced by decreased osteoclast number in vivo and impaired osteoclast formation in vitro. The decreased osteoclast formation was accompanied by down-regulated expression of osteoclastogenic genes, compromised chemokine receptor signaling, and an increase in apoptosis during osteoclast differentiation. Together, these data suggest that PI3Kγ regulates bone homeostasis by modulating osteoclastogenesis. Our study also suggests that inhibition of PI3Kγ, which is being considered as a potential therapeutic strategy for treating chronic inflammatory disorders, may result in an increase in bone mass. Class I PI3Ks are further divided into class IA and IB. Class IA PI3K catalytic subunits (p110α, p110β, and p110δ) form a heterodimeric complex with one of the regulatory subunits (p85α, p55α, p50α, p85β, and p55γ). Src homology 2 (SH2) domains in the regulatory subunits bridge class IA PI3Ks to tyrosine kinase receptors and cytoplasmic tyrosine kinases. In contrast, PI3Kγ (p110γ), the sole member of class IB PI3K, interacts with p101 regulatory subunit and is a key signaling player downstream of seven transmembrane G protein-coupled receptors (GPCRs). Stimulation of GPCRs triggers interaction of PI3Kγ and G βγ subunits of heterotrimeric G proteins (2, 3). PI3Kγ was found at high levels in hematopoietic cells and also detected in the heart, endothelium, and brain. Studies with PI3Kγ knockout (KO) mice and kinase-dead knock-in mice have substantially advanced our understanding of the role of PI3Kγ-mediated signaling in leukocytes and cardiomyocytes and suggested PI3Kγ as a promising drug target for treatment of inflammatory diseases and cardioprotective therapy.Given the recent development of selective PI3Kγ inhibitors, of which effectiveness was verified in experimental animal models of diseases (4, 5), the question arises as to whether PI3Kγ inhibition affects bone homeostasis. Bone homeostasis is maintained via the balance between bone formation by osteoblasts and bone resorption by osteoclasts. Osteoclasts are multinucleated cells specialized in bone resorption. Osteoclast precursors differentiate from monocyte-macrophage lineage cells of hematopoietic origin and undergo cell fusion process to become multinucleated mature osteoclasts. Receptor activator of NF-κB (RANK) signaling triggered by RANK ligand (RANKL) activa...

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Section: Discussionmentioning

confidence: 99%

Important roles of PI3Kγ in osteoclastogenesis and bone homeostasis

Kang

Chang

Hurley

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…CCL2 has been shown to stimulate the formation of osteoclasts (although it is not sufficient for the osteoclasts to be fully active). 33,34 Moreover, CCL2, also known as monocyte chemotactic protein-1, has long been known to recruit monocytes/macrophages. 35 Thus, in Gaucher disease, an increased secretion of CCL2 by MSCs could contribute to the recruitment of monocytes and their transformation in osteoclasts at sites of bone disease.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Gaucher disease bone marrow mesenchymal stromal cells reveals an altered inflammatory secretome

Campeau

Rafei²,

Boivin³

et al. 2009

Blood

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“…36 The calcitonin receptor is an osteoclast differentiation marker. 29 Osteoclast differentiation is thought to be initiated before the deposition of cartilage or bone matrix as calcitonin-binding cells appear before cartilage and bone formation in the area of ectopic bone formation induced by BMP. 25 Nell1 is a protein strongly present in cells of neural crest origin residing within the craniofacial complex.…”

Section: Discussionmentioning

confidence: 99%

Pressure and Distortion Regulate Human Mesenchymal Stem Cell Gene Expression

et al. 2009

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Abstract-While the concept that physical forces such as tension and compression are involved in mature tissue modeling is widely accepted, the role of these specific types of mechanical loading in the differentiation and maturation of uncommitted cell types like human mesenchymal stem cells (hMSCs) is currently unknown. We observed that hMSCs have the fundamental ability to distinguish between dynamic tensile and compressive loading by regulating distinct gene expression patterns and that these differences in gene expression can be related to conformational changes in cell shape and volume. Dynamic tension was found to regulate both fibroblastic and osteogenic associated genes while dynamic compression up-regulated genes associated with chondrogenesis. Identifying genes involved in the mechanotransduction of different modes of physical loading in hMSC may greatly enhance the ability to rationally design tissue regeneration systems to restore proper tissue function.

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MCP-1-induced Human Osteoclast-like Cells Are Tartrate-resistant Acid Phosphatase, NFATc1, and Calcitonin Receptor-positive but Require Receptor Activator of NFκB Ligand for Bone Resorption

Abstract: MCP-1 (monocyte chemotactic protein-1) is a CC

Cited by 132 publications

References 28 publications

Important roles of PI3Kγ in osteoclastogenesis and bone homeostasis

Important roles of PI3Kγ in osteoclastogenesis and bone homeostasis

Characterization of Gaucher disease bone marrow mesenchymal stromal cells reveals an altered inflammatory secretome

Pressure and Distortion Regulate Human Mesenchymal Stem Cell Gene Expression

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