PMID- 27646989 OWN - NLM STAT- MEDLINE DCOM- 20180604 LR - 20181113 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 6 DP - 2016 Sep 20 TI - Ablation of Y1 receptor impairs osteoclast bone-resorbing activity. PG - 33470 LID - 10.1038/srep33470 [doi] LID - 33470 AB - Y1 receptor (Y1R)-signalling pathway plays a pivotal role in the regulation of bone metabolism. The lack of Y1R-signalling stimulates bone mass accretion that has been mainly attributed to Y1R disruption from bone-forming cells. Still, the involvement of Y1R-signalling in the control of bone-resorbing cells remained to be explored. Therefore, in this study we assessed the role of Y1R deficiency in osteoclast formation and resorption activity. Here we demonstrate that Y1R germline deletion (Y1R(-/-)) 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 Y1R(-/-) 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 Y1R(-/-) resorption pits displayed a marked reduction in surface area, volume and depth. Together, these data demonstrates that the lack of Y1Rs 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 Y1R-signalling ablation. FAU - Sousa, Daniela M AU - Sousa DM AD - Instituto de Investigacao e Inovacao em Saude (i3S), Universidade do Porto, NanoBiomaterials for targeted therapies Group, Rua Alfredo Allen 208, 4200-135 Porto, Portugal. AD - Instituto de Engenharia Biomedica (INEB), Universidade do Porto, Porto, Portugal. FAU - Conceicao, Francisco AU - Conceicao F AD - Instituto de Investigacao e Inovacao em Saude (i3S), Universidade do Porto, NanoBiomaterials for targeted therapies Group, Rua Alfredo Allen 208, 4200-135 Porto, Portugal. AD - Instituto de Engenharia Biomedica (INEB), Universidade do Porto, Porto, Portugal. AD - Instituto de Ciencias Biomedicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal. FAU - Silva, Diana I AU - Silva DI AD - Instituto de Engenharia Biomedica (INEB), Universidade do Porto, Porto, Portugal. FAU - Leitao, Luis AU - Leitao L AD - Instituto de Investigacao e Inovacao em Saude (i3S), Universidade do Porto, NanoBiomaterials for targeted therapies Group, Rua Alfredo Allen 208, 4200-135 Porto, Portugal. AD - Instituto de Engenharia Biomedica (INEB), Universidade do Porto, Porto, Portugal. AD - Instituto de Ciencias Biomedicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal. FAU - Neto, Estrela AU - Neto E AD - Instituto de Investigacao e Inovacao em Saude (i3S), Universidade do Porto, NanoBiomaterials for targeted therapies Group, Rua Alfredo Allen 208, 4200-135 Porto, Portugal. AD - Instituto de Engenharia Biomedica (INEB), Universidade do Porto, Porto, Portugal. AD - Faculdade de Medicina da Universidade do Porto (FMUP), Porto, Portugal. FAU - Alves, Cecilia J AU - Alves CJ AD - Instituto de Investigacao e Inovacao em Saude (i3S), Universidade do Porto, NanoBiomaterials for targeted therapies Group, Rua Alfredo Allen 208, 4200-135 Porto, Portugal. AD - Instituto de Engenharia Biomedica (INEB), Universidade do Porto, Porto, Portugal. FAU - Alencastre, Ines S AU - Alencastre IS AD - Instituto de Investigacao e Inovacao em Saude (i3S), Universidade do Porto, NanoBiomaterials for targeted therapies Group, Rua Alfredo Allen 208, 4200-135 Porto, Portugal. AD - Instituto de Engenharia Biomedica (INEB), Universidade do Porto, Porto, Portugal. FAU - Herzog, Herbert AU - Herzog H AD - Neuroscience Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia. FAU - Aguiar, Paulo AU - Aguiar P AD - Instituto de Investigacao e Inovacao em Saude (i3S), Universidade do Porto, NanoBiomaterials for targeted therapies Group, Rua Alfredo Allen 208, 4200-135 Porto, Portugal. AD - Instituto de Engenharia Biomedica (INEB), Universidade do Porto, Porto, Portugal. AD - Centro de Matematica da Universidade do Porto, Departamento de Matematica da Faculdade de Ciencias da Universidade do Porto (FCUP), Porto, Portugal. FAU - Lamghari, Meriem AU - Lamghari M AD - Instituto de Investigacao e Inovacao em Saude (i3S), Universidade do Porto, NanoBiomaterials for targeted therapies Group, Rua Alfredo Allen 208, 4200-135 Porto, Portugal. AD - Instituto de Engenharia Biomedica (INEB), Universidade do Porto, Porto, Portugal. AD - Instituto de Ciencias Biomedicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160920 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - 0 (Minerals) RN - 0 (Receptors, Neuropeptide) SB - IM MH - Animals MH - Bone Matrix/metabolism MH - Bone Resorption/*metabolism MH - Cell Fusion MH - Cell Size MH - *Gene Deletion MH - Gene Expression Profiling MH - Mice, Inbred C57BL MH - Minerals/metabolism MH - Osteoclasts/*metabolism MH - Osteogenesis/genetics MH - Receptors, Neuropeptide/genetics/*metabolism MH - Signal Transduction MH - Up-Regulation/genetics PMC - PMC5028844 EDAT- 2016/09/21 06:00 MHDA- 2018/06/05 06:00 PMCR- 2016/09/20 CRDT- 2016/09/21 06:00 PHST- 2016/04/25 00:00 [received] PHST- 2016/08/24 00:00 [accepted] PHST- 2016/09/21 06:00 [entrez] PHST- 2016/09/21 06:00 [pubmed] PHST- 2018/06/05 06:00 [medline] PHST- 2016/09/20 00:00 [pmc-release] AID - srep33470 [pii] AID - 10.1038/srep33470 [doi] PST - epublish SO - Sci Rep. 2016 Sep 20;6:33470. doi: 10.1038/srep33470.