Integrin‐associated molecules and signalling cross talking in osteoclast cytoskeleton regulation

Kong, Lingbo; Wang, Biao; Yang, Xiaobin; He, Baorong; Hao, Dingjun; Yan, Liang

doi:10.1111/jcmm.15052

Cited by 44 publications

(26 citation statements)

References 108 publications

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“…5A, B). Integrin β 3 and c-Src are highly expressed during osteoclast fusion and are required for osteoclast migration [37]. Here, we show that although integrin β 3 and c-Src expression levels gradually increase during osteoclast fusion, alpinetin treatment remarkably suppressed their expression ( Fig.…”

Section: Alpinetin Inhibits Osteoclast Activity By Modulating Integrisupporting

confidence: 50%

Alpinetin Inhibits RANKL-Induced Osteoclastogenesis and Ovariectomy-Induced Bone Loss by Modulating NFATc1 Transcription and Lysosomal Function

Chen

et al. 2020

Preprint

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BackgroundPostmenopausal osteoporosis is a chronic metabolic bone disease caused by excessive osteoclast activation, and osteoclasts are considered to be the sole participants in the degeneration and resorption of bone matrix for controlling bone integrity and continuity. The biological functions of osteoclasts depend critically on the number and activity of fused polykaryon. Hence, targeting osteoclast differentiation and activity can modulate bone resorption and alleviate osteoporosis. Alpinetin is widely used for excellent anti-inflammatory activities and little side-effect, but its role in osteoporosis remains unknown.ResultsIn this study, we investigated for the first time the ability of alpinetin to inhibit estrogen deficiency-induced bone loss. Alpinetin significantly reduced the expression levels of NFATc1 and its downstream genes, thereby inhibiting osteoclast differentiation in a concentration- and time-dependent manner. Additionally, alpinetin inhibited F-actin ring formation and bone resorption, as well as reduced the activation levels of NF-κB, ERK, and AKT signaling cascades. In mature osteoclasts, alpinetin remarkably inhibited integrin-mediated migration and lysosomal biogenesis and trafficking by modulating the PKCβ/TFEB and ATG5/LC3 axes. Importantly, alpinetin treatment in mice alleviated ovariectomy-induced bone volume loss. ConclusionOur findings strongly suggest that alpinetin plays a significant role in the regulation of NFATc1 production for the differentiation of osteoclasts and inhibits integrin-mediated cell migration and lysosomal function in mature osteoclasts, thus weaken the increased osteolytic ability due to estrogen deficiency. Alpinetin may represent a promising agent for the treatment of osteoporosis and other metabolic bone diseases.

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Section: Alpinetin Inhibits Osteoclast Activity By Modulating Integrisupporting

confidence: 50%

Alpinetin Inhibits RANKL-Induced Osteoclastogenesis and Ovariectomy-Induced Bone Loss by Modulating NFATc1 Transcription and Lysosomal Function

Chen

et al. 2020

Preprint

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“…Macrophage colony stimulating factor (M-CSF, also known as CSF1) is required by preosteoclasts for survival, proliferation and osteoclastic differentiation, whereas the receptor activator of nuclear factor-kappaB ligand (RANKL), another key osteoclastogenesis cytokine, is responsible for osteoclast formation and the activation of osteoclastic resorptive function ( Kong et al, 2020 ). Therefore, we evaluated the level of M-CSF and RANKL in serum.…”

Section: Resultsmentioning

confidence: 99%

Akkermansia muciniphila promotes type H vessel formation and bone fracture healing by reducing gut permeability and inflammation

Liu

Tao

Luo

et al. 2020

Disease Models &Amp; Mechanisms

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Improving revascularization is one of the major measures in fracture treatment. Moderate local inflammation triggers angiogenesis, whereas systemic inflammation hampers angiogenesis. Previous studies showed that Akkermansia muciniphila (A. muc), a gut probiotic, ameliorates systemic inflammation by tightening intestinal barrier. In this study, fractured mice intragastrically administrated with A. muc were found to display better fracture healing than mice treated with vehicle. Notably, more preosteclasts positive for platelet-derived growth factor-BB (PDGF-BB) were induced by A. muc at 2 weeks post fracture, coinciding with increased formation of type H vessels, a specific vessel subtype that couples angiogenesis and osteogenesis and can be stimulated by PDGF-BB. Moreover, A. muc treatment significantly reduced gut permeability and inflammation at early stage. Dextran Sulfate Sodium (DSS) was used to disrupt the gut barrier to determine the role of gut barrier in fracture healing and whether A. muc still can stimulate bone fracture healing. As expected, A. muc evidently improved gut barrier, reduced inflammation, and restored the impaired bone healing and angiogenesis in DSS-treated mice. Our results suggest that A. muc reduces intestinal permeability and alleviates inflammation, which probably induces more PDGF-BB positive preosteoclasts and type H vessel formation in callus, thereby promoting fracture healing. This study provides the evidences about the involvement of type H vessels in fracture healing and suggests the potential of A. muc as a promising strategy for bone healing.

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“…Furthermore, GPR55 has been reported to regulate CB 2 -mediated chemotaxis of human neutrophils [57] and to modulate migration and polarisation of human breast cancer cells [58]. Therefore, as actin remodelling and cell migration are essential for osteoclast cell-to-cell fusion [59], these systems might explain the effects of GPR55 silencing on osteoclast syncytium formation.…”

Section: Discussionmentioning

confidence: 99%

Peptide targeting of the lysolipid-sensing GPR55 for osteoclastogenesis tuning

Mosca¹,

Mangini²,

Barba³

et al. 2020

Preprint

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Background: The G-protein-coupled receptor GPR55 has been implicated in multiple biological activities, which has fuelled interest in its functional targeting. Its controversial pharmacology and the regulation often species dependent impacted the potential translation of preclinical data involving GPR55.Results: With the aim to identify novel GPR55 regulators, we have started investigating the lysophosphatidylinositol (LPI)-induced GPR55-mediated signal transduction. HeLa cells silenced for their endogenous receptor, by stable expression of a short-hairpin RNA specific for GPR55 5’-UTR, were the expression system for wild-type and mutated GPR55 that allowed the definition of the requirement of GPR55 Lys80 for LPI-induced MAPK activation and receptor internalisation. In RAW264.7 macrophages, GPR55 pathways were investigated by Gpr55 silencing using small-interfering RNAs, demonstrating that LPI increased intracellular Ca2+ levels and induced actin filopodium formation through GPR55 activation. Furthermore, LPI/GPR55 axis was shown to have an active role in the osteoclastogenesis of precursor RAW264.7 cells induced by the ‘receptor-activator of nuclear factor kappa-B ligand’ (RANKL). Indeed, this differentiation into mature osteoclasts was associated with 14-fold increase in Gpr55 mRNA levels. Moreover, GPR55 silencing or antagonism impaired the RANKL-induced transcription of the osteoclastogenesis markers: ‘nuclear factor of activated T-cells, cytoplasmic 1’, matrix metalloproteinase-9, cathepsin-K, tartrate-resistant acid phosphatase, and the calcitonin receptor, as evaluated by real-time PCR. Phage display was previously used to identify peptides that bind to GPR55. Here, the GPR55-specific peptide-P1 strongly inhibited osteoclast maturation of RAW264.7 macrophages.Conclusions: As bone-metastasis development can be blocked through inhibition of bone resorption, osteoclasts are strong targets for anti-metastatic treatments, and such GPR55-specific peptides might represent useful tools for novel therapeutic approaches.

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Integrin‐associated molecules and signalling cross talking in osteoclast cytoskeleton regulation

Cited by 44 publications

References 108 publications

Alpinetin Inhibits RANKL-Induced Osteoclastogenesis and Ovariectomy-Induced Bone Loss by Modulating NFATc1 Transcription and Lysosomal Function

Alpinetin Inhibits RANKL-Induced Osteoclastogenesis and Ovariectomy-Induced Bone Loss by Modulating NFATc1 Transcription and Lysosomal Function

Akkermansia muciniphila promotes type H vessel formation and bone fracture healing by reducing gut permeability and inflammation

Peptide targeting of the lysolipid-sensing GPR55 for osteoclastogenesis tuning

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