Ablation of Y(1) receptor impairs osteoclast bone-resorbing activity

Y(1) receptor (Y(1)R)-signalling pathway plays a pivotal role in the regulation of bone metabolism. The lack of Y(1)R-signalling stimulates bone mass accretion that has been mainly attributed to Y(1)R disruption from bone-forming cells. Still, the involvement of Y(1)R-signalling in the control of bone-resorbing cells remained to be explored. Therefore, in this study we assessed the role of Y(1)R deficiency in osteoclast formation and resorption activity. Here we demonstrate that Y(1)R germline deletion (Y(1)R(−/−)) led to increased formation of highly multinucleated (n > 8) osteoclasts and enhanced surface area, possibly due to monocyte chemoattractant protein-1 (MCP-1) overexpression regulated by RANKL-signalling. Interestingly, functional studies revealed that these giant Y(1)R(−/−) multinucleated cells produce poorly demineralized eroded pits, which were associated to reduce expression of osteoclast matrix degradation markers, such as tartrate-resistant acid phosphatase-5b (TRAcP5b), matrix metalloproteinase-9 (MMP-9) and cathepsin-K (CTSK). Tridimensional (3D) morphologic analyses of resorption pits, using an in-house developed quantitative computational tool (BonePit), showed that Y(1)R(−/−) resorption pits displayed a marked reduction in surface area, volume and depth. Together, these data demonstrates that the lack of Y(1)Rs stimulates the formation of larger multinucleated osteoclasts in vitro with reduced bone-resorbing activity, unveiling a novel therapeutic option for osteoclastic bone diseases based on Y(1)R-signalling ablation.