Tumor Necrosis Factor alpha (TNF-α) plays a role in several chronic immune and inﬂammatory diseases, where inhibition of TNF has led to signiﬁcant clinical improvement. Actually, this cytokine is involved in bone healing by affecting mesenchymal stem cell (MSC) behaviour in a dose- and time-dependent manner1,2. Indeed, in the early inflammatory phase after fracture, low doses of TNF-α are required to favour MSC migration, survival and differentiation, thus initiating bone repair. At high dose, in the chronic uncontrolled phase of inflammation, the same cytokine has destructive effects on bone and contribute to bone loss1,2. As other soluble factors released in cell microenvironment, the cytokine modulates expression and functioning of different G protein coupled receptors (GPCRs) and of their regulatory proteins (GPCR regulated kinases, GRKs)3, thus dictating the final biological outcome of these receptor proteins in controlling bone anabolic processes. Herein, we investigated the effects of TNF-α low doses on the expression and functional responsiveness of A2B adenosine receptor (A2B AR), a Gs-coupled puringergic receptor that controls mesenchymal stem cell (MSC) differentiation to osteoblasts4,5. In our hands, TNF-α exerted a pro-differentiating action on MSCs, pushing towards an osteoblast phenotype, and without any effects on cell proliferation. The cytokine increased the A2B AR-mediated pro-osteogenic effects, through the A2B AR desensitization impairment mediated by GRK2 inhibition. These data i) support the anabolic effect of sub-massimal concentration of TNF-α in bone reparative processes and ii) demonstrate that the cytokine regulates GPCR responses by interfering with desensitization machinery and potentiating in turn the anabolic responses evoked by Gs-GPCRs. Overall these results indicated that manipulating MSC local environment by lregulates membrane receptors favouring bone remodelling.
|Titolo:||TUMOR NECROSIS FACTOR ALPHA TRIGGERS OSTEOGENESIS THROUGH THE INVOVLVEMENT OF Gs-COUPLED RECEPTOR SIGNALS|
|Anno del prodotto:||2016|
|Appare nelle tipologie:||4.2 Abstract in Atti di convegno|