Abstract:
:In the early phase of bone damage, low concentrations of the cytokine tumor necrosis factor alpha (TNF-α) favor osteoblast differentiation. In contrast, chronic high doses of the same cytokine contribute to bone loss, demonstrating opposite effects depending on its concentration and on the time of exposure. In the bone microenvironment, TNF-α modulates the expression/function of different G protein-coupled receptors (GPCRs) and of their regulatory proteins, GPCR-regulated kinases (GRKs), thus dictating their final biological outcome in controlling bone anabolic processes. Here, the effects of TNF-α were investigated on the expression/responsiveness of the A2B adenosine receptor (A2BAR), a Gs-coupled receptor that promotes mesenchymal stem cell (MSC) differentiation into osteoblasts. Low TNF-α concentrations exerted a prodifferentiating effect on MSCs, pushing them toward an osteoblast phenotype. By regulating GRK2 turnover and expression, the cytokine impaired A2BAR desensitization, accelerating receptor-mediated osteoblast differentiation. These data supported the anabolic effect of TNF-α submaximal concentration and demonstrated that the cytokine regulates GPCR responses by interfering with the receptor desensitization machinery, thereby enhancing the anabolic responses evoked by A2BAR ligands. Overall, these results indicated that GPCR desensitization plays a pivotal role in osteogenesis and that its manipulation is an effective strategy to favor bone remodeling.
journal_name
Mol Cell Bioljournal_title
Molecular and cellular biologyauthors
Daniele S,Natali L,Giacomelli C,Campiglia P,Novellino E,Martini C,Trincavelli MLdoi
10.1128/MCB.00442-16subject
Has Abstractpub_date
2017-03-31 00:00:00issue
8eissn
0270-7306issn
1098-5549pii
MCB.00442-16journal_volume
37pub_type
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journal_title:Molecular and cellular biology
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journal_title:Molecular and cellular biology
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pub_type: 杂志文章
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pub_type: 杂志文章
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pub_type: 杂志文章
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journal_title:Molecular and cellular biology
pub_type: 杂志文章
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journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.15.11.6075
更新日期:1995-11-01 00:00:00
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pub_type: 杂志文章
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