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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 &gt; 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.

Ablation of Y1 receptor impairs osteoclast bone-resorbing activity