Coordination of osteoclast‐osteoblast differentiation by transglutaminase 2

Enzyme transglutaminase 2 (TG2) promotes maturation of committed osteoblasts in vitro. Nevertheless, TG2 null mice have no skeletal phenotype. Here, we tested the hypothesis that TG2 regulates differentiation in both osteoblasts and osteoclasts with mutually attenuating effects, resulting in the maintenance of status quo between bone formation and resorption. Differentiation of bone marrow‐derived progenitors into osteoblasts and osteoclasts was compared in TG2−/− and wild‐type mice. A significant 25+/− 7% (p<0.001) decrease in the osteoblast colony formation and a dramatic 50+/−15% (p<0.01) decrease in the number of tartrate‐resistant acid phosphatase (TRAP)‐positive colonies was detected in the TG2−/− bone marrow as compared to the wild‐type. Similarly, osteoblast differentiation was delayed in the TG2−/− BMSCs with an 80% reduction in expression of bone sialoprotein and alkaline phosphatase. Further, exogenous purified TG2 accelerated differentiation of the wild‐type progenitors into both osteoblasts and osteoclasts, while the TG2‐specific inhibitor KCC‐009 quenched the TG2‐induced increase in the number of the wildtype osteoclast TRAP‐positive colonies and the number of multinucleated osteoclasts. These data demonstrate a new role for TG2 in coordinating osteoblast‐osteoclast crosstalk and differentiation. This research was supported by NIH grants R03AR057126 and 1R56DK71920.