title: Ablation of Y1 receptor impairs osteoclast bone-resorbing activity.
abstract: 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.
authors.affiliation: Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, NanoBiomaterials for targeted therapies Group, Rua Alfredo Allen 208, 4200-135 Porto, Portugal.|Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal.
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Sousa
authors.affiliation: Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, NanoBiomaterials for targeted therapies Group, Rua Alfredo Allen 208, 4200-135 Porto, Portugal.|Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal.|Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.
authors.forename: Francisco
authors.initials: F
authors.lastname: Conceição
authors.affiliation: Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal.
authors.forename: Diana I
authors.initials: DI
authors.lastname: Silva
authors.affiliation: Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, NanoBiomaterials for targeted therapies Group, Rua Alfredo Allen 208, 4200-135 Porto, Portugal.|Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal.|Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.
authors.forename: Luís
authors.initials: L
authors.lastname: Leitão
authors.affiliation: Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, NanoBiomaterials for targeted therapies Group, Rua Alfredo Allen 208, 4200-135 Porto, Portugal.|Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal.|Faculdade de Medicina da Universidade do Porto (FMUP), Porto, Portugal.
authors.forename: Estrela
authors.initials: E
authors.lastname: Neto
authors.affiliation: Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, NanoBiomaterials for targeted therapies Group, Rua Alfredo Allen 208, 4200-135 Porto, Portugal.|Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal.
authors.forename: Cecília J
authors.initials: CJ
authors.lastname: Alves
authors.affiliation: Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, NanoBiomaterials for targeted therapies Group, Rua Alfredo Allen 208, 4200-135 Porto, Portugal.|Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal.
authors.forename: Inês S
authors.initials: IS
authors.lastname: Alencastre
authors.affiliation: Neuroscience Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia.
authors.forename: Herbert
authors.initials: H
authors.lastname: Herzog
authors.affiliation: Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, NanoBiomaterials for targeted therapies Group, Rua Alfredo Allen 208, 4200-135 Porto, Portugal.|Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal.|Centro de Matemática da Universidade do Porto, Departamento de Matemática da Faculdade de Ciências da Universidade do Porto (FCUP), Porto, Portugal.
authors.forename: Paulo
authors.initials: P
authors.lastname: Aguiar
authors.affiliation: Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, NanoBiomaterials for targeted therapies Group, Rua Alfredo Allen 208, 4200-135 Porto, Portugal.|Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal.|Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.
authors.forename: Meriem
authors.initials: M
authors.lastname: Lamghari
mesh_terms: D000818:Animals; D001857:Bone Matrix / Q000378:metabolism; D001862:Bone Resorption / Q000378:metabolism*; D002459:Cell Fusion; D048429:Cell Size; D017353:Gene Deletion; D020869:Gene Expression Profiling; D008810:Mice, Inbred C57BL; D008903:Minerals / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism*; D010012:Osteogenesis / Q000235:genetics; D018013:Receptors, Neuropeptide / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation / Q000235:genetics
chemical_list: D008903:Minerals; D018013:Receptors, Neuropeptide