The A2B adenosine receptor (A2BAR) has been recently emerged as the major adenosine receptor involved in the mesenchymal stem cell differentiation to osteoblast and bone formation, highlighting this receptor as a new target in bone diseases. In the present study, we characterized a new 3-keto-indole-derivative (KI-7) as the first positive allosteric modulator (PAM) of the human A2B AR in mesenchymal stem cells (MSCs), and we investigated the potential activity of this compound as osteogenic agent. KI-7 was able to increase the effects of A2B AR of both endogenous and orthosteric agonists on the expression of osteogenic markers and on osteoblast mineralization. In the early phase of differentiation program, KI-7 significantly potentiated physiological and A2B agonist-mediated down-regulation of IL-6 release. Conversely, during the late stage of differentiation, when most of the cells have an osteoblast phenotype, KI-7 caused a sustained raise in IL-6 levels and an improvement in osteoblast viability. These data suggest that positive allosteric modulation of A2B AR not only favors MSC commitment to osteoblasts, but also ensures a greater survival of mature osteoblasts. Our study paves the way for a therapeutic use of selective positive allosteric modulators of A2B AR in the control of osteoblast differentiation, bone formation and fracture repair.
The mesenchymal stem cell differentiation to osteoblasts is potentiate by the allosteric modulation of A2B adenosine receptors.
DANIELE, SIMONA;TRINCAVELLI, MARIA LETIZIA;GIACOMELLI, CHIARA;NATALI, LETIZIA;TALIANI, SABRINA;DA SETTIMO PASSETTI, FEDERICO;MARTINI, CLAUDIA
2015-01-01
Abstract
The A2B adenosine receptor (A2BAR) has been recently emerged as the major adenosine receptor involved in the mesenchymal stem cell differentiation to osteoblast and bone formation, highlighting this receptor as a new target in bone diseases. In the present study, we characterized a new 3-keto-indole-derivative (KI-7) as the first positive allosteric modulator (PAM) of the human A2B AR in mesenchymal stem cells (MSCs), and we investigated the potential activity of this compound as osteogenic agent. KI-7 was able to increase the effects of A2B AR of both endogenous and orthosteric agonists on the expression of osteogenic markers and on osteoblast mineralization. In the early phase of differentiation program, KI-7 significantly potentiated physiological and A2B agonist-mediated down-regulation of IL-6 release. Conversely, during the late stage of differentiation, when most of the cells have an osteoblast phenotype, KI-7 caused a sustained raise in IL-6 levels and an improvement in osteoblast viability. These data suggest that positive allosteric modulation of A2B AR not only favors MSC commitment to osteoblasts, but also ensures a greater survival of mature osteoblasts. Our study paves the way for a therapeutic use of selective positive allosteric modulators of A2B AR in the control of osteoblast differentiation, bone formation and fracture repair.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
