Targeting Integrin-β1 Impedes Cytokine-Induced Osteoclast Differentiation: A Potential Pharmacological Intervention in Pathological Osteolysis

Lü, Xing; Zhang, Xinglin; Chu, Kai On; Zhang, Guodong; Zheng, Yunfei

doi:10.4314/tjpr.v15i2.11

Cited by 3 publications

(1 citation statement)

References 21 publications

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“…Integrin β1 serves as an important signaling receptor and adhesion molecule in platelets, but conditional β1 KO studies in bone cells have largely been limited to osteoblasts and their precursors, all which display mild to moderate phenotypes ( Petzold et al, 2013 ; Shekaran et al, 2014 ; Habart et al, 2013 ; Zimmerman et al, 2000 ; Globus et al, 2005 ; Litzenberger et al, 2010 ). In vitro , integrin β1 is essential for TNF-α-induced osteoclastogenesis, while RANKL-induced osteoclastogenesis is unaffected ( Lu et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Regulation of cytoskeleton and adhesion signaling in osteoclasts by tetraspanin CD82

et al. 2019

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We used a myeloid-specific Cre to conditionally delete CD82 in mouse osteoclasts and their precursors. In contrast to global loss of CD82 (gKO), conditional loss of CD82 (cKO) in osteoclasts does not affect cortical bone, osteoblasts, or adipocytes. CD82 loss results in greater trabecular volume and trabecular number but reduced trabecular space in 6-month old male mice. Though this trend is present in females it did not reach significance; whereas there was an increase in osteoclast numbers and eroded surface area only in female cKO mice. In vitro, there is an increase in osteoclast fusion and defects in actin assembly in both gKO and cKO mice, irrespective of sex. This is accompanied by altered osteoclast morphology and decreased release of CTX in vitro. Integrin αvβ3 expression is reduced, while integrin β1 is increased. Signaling to Src, Syk, and Vav are also compromised. We further discovered that expression of Clec2 and its ligand, Podoplanin, molecules that also signal to Syk and Vav, are increased in differentiated osteoclasts. Loss of CD82 reduces their expression. Thus, CD82 is required for correct assembly of the cytoskeleton and to limit osteoclast fusion, both needed for normal osteoclast function.

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Section: Discussionmentioning

confidence: 99%

Regulation of cytoskeleton and adhesion signaling in osteoclasts by tetraspanin CD82

et al. 2019

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Obacunone inhibits RANKL/M-CSF-mediated osteoclastogenesis by suppressing integrin- FAK-Src signaling

Wang

Huang

et al. 2023

Cytokine

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Integrin α2 is an early marker for osteoclast differentiation that contributes to key steps in osteoclastogenesis

Brockhaus,

Hemsen,

Jauch-Speer

et al. 2024

Front. Cell Dev. Biol.

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IntroductionOsteoclasts determine bone tissue turnover. Their increased activity causes osteoporosis, their dysfunction osteopetrosis.Methods and ResultsMurine monocytic ER-Hoxb8 cells differentiate into OCs upon treatment with M-CSF and RANKL and upregulate the collagen-binding integrin α2β1 distinctly earlier than other OC markers, such as the OC-associated receptor, OSCAR. Integrin α2β1 promotes OC differentiation at multiple levels by stimulating differentiation-relevant genes, by regulating cell matrix adhesion and the formation of adhesion-promoting protrusions, and by the upregulation of proteins involved in precursor cell fusion. The two key factors in osteoclastogenesis, RANK and NFATc1, were essentially unaffected after knocking out the ITGA2 gene encoding integrin α2 subunit. However, compared to integrin α2β1 expressing ER-Hoxb8 cells, ITGA2-deficient cells adhered differently with more branched filopodia and significantly longer tunneling nanotubes. Despite the higher number of fusion-relevant TNTs, they form fewer syncytia. They also resorb less hydroxyapatite, because integrin α2β1 regulates expression of lacuna proteins necessary for bone matrix resorption. The impaired syncytia formation of ITGA2-deficient OC precursor cells also correlated with reduced gene activation of fusion-supporting DC-STAMP and with an almost abolished transcription of tetraspanin CD9. CD9 only partially colocalized with integrin α2β1 in TNTs and filopodia of integrin α2β1-expressing OC precursors.DiscussionOur findings define integrin α2β1 as an early marker of OC differentiation.

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Targeting Integrin-β1 Impedes Cytokine-Induced Osteoclast Differentiation: A Potential Pharmacological Intervention in Pathological Osteolysis

Abstract: Purpose: To examine whether integrin-β1 is essential for osteoclast differentiation and function and if it

Cited by 3 publications

References 21 publications

Regulation of cytoskeleton and adhesion signaling in osteoclasts by tetraspanin CD82

Regulation of cytoskeleton and adhesion signaling in osteoclasts by tetraspanin CD82

Obacunone inhibits RANKL/M-CSF-mediated osteoclastogenesis by suppressing integrin- FAK-Src signaling

Integrin α2 is an early marker for osteoclast differentiation that contributes to key steps in osteoclastogenesis

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