CD73‐generated adenosine promotes osteoblast differentiation

Abstract

CD73 is a GPI-anchored cell surface protein with ecto-5′-nucleotidase enzyme activity that plays a crucial role in adenosine production. While the roles of adenosine receptors (AR) on osteoblasts and osteoclasts have been unveiled to some extent, the roles of CD73 and CD73-generated adenosine in bone tissue are largely unknown. To address this issue, we first analyzed the bone phenotype of CD73-deficient (cd73−/−) mice. The mutant male mice showed osteopenia, with significant decreases of osteoblastic markers. Levels of osteoclastic markers were, however, comparable to those of wild type mice. A series of in vitro studies revealed that CD73 deficiency resulted in impairment in osteoblast differentiation but not in the number of osteoblast progenitors. In addition, over expression of CD73 on MC3T3-E1 cells resulted in enhanced osteoblastic differentiation. Moreover, MC3T3-E1 cells expressed adenosine A2A receptors (A2AAR) and A2B receptors (A2BAR) and expression of these receptors increased with osteoblastic differentiation. Enhanced expression of osteocalcin (OC) and bone sialoprotein (BSP) observed in MC3T3-E1 cells over expressing CD73 were suppressed by treatment with an A2BAR antagonist but not with an A2AAR antagonist. Collectively, our results indicate that CD73 generated adenosine positively regulates osteoblast differentiation via A2BAR signaling.

Direct or indirect stimulation of adenosine A 2A receptors enhances bone regeneration as well as bone morphogenetic protein‐2

“…To date, strong evidence has implicated A2BR in osteoblast differentiation and function (20,22,(32)(33)(34), but little evidence supports a role for either A1R or A2AR in the regulation of osteoblast differentiation or function. Thus, Gharibi et al (35) reported that, although A1R was expressed in osteoblast precursors, it was involved in induction of adipocyte differentiation rather than osteoblast differentiation.…”

The role of purinergic signalling in the musculoskeletal system

“…Furthermore, a synthetic A2B receptor agonist has been shown to increase bone formation, and osteoblasts from A2B receptor knockout mice display reduced activity in vitro (Carroll et al, 2012). Recently, it was reported that the adenosine generated by ecto-5'-nucleotidase (CD-73) was important in promoting osteoblast differentiation (Takedachi et al, 2012). In contrast, adenosine analogues, acting via the A1 or A2A receptors, have been shown to inhibit the differentiation of rodent osteoblast-like cells (Gharibi et al, 2012).…”

Regulation of bone and cartilage by adenosine signaling

“…Without these enzymes, bone development fails to progress normally. For example, CD73 knockout mice are osteopenic and have diminished osteoblast function [27].…”

“…Similarly, Takedachi et al proposed that CD73 promotes osteoblast development through A2BR but not A2AR. Using MC3T3-E1 cells that overexpressed CD73, these researchers showed that treatment with an A2BR antagonist suppressed bone sialoprotein and osteocalcin levels, while this effect was not observed with an A2AR antagonists [27].…”