The lack of neuropeptide y-y 1 receptor signaling modulates the chemical and mechanical properties of bone matrix
Daniela M. Sousa, Pedro S. Martins, Luís Leitão, Cecília J. Alves, Maria Gomez-Lazaro, Estrela Neto, Francisco Conceição, Herbert Herzog, and Meriem Lamghari. The lack of neuropeptide y-y 1 receptor signaling modulates the chemical and mechanical properties of bone matrix. The FASEB Journal, 34(3):4163–4177, jan 2020. doi: 10.1096/fj.201902796r
Genetic and pharmacological functional studies have provided evidence that the lack of Neuropeptide Y-Y1 receptor (Y1R) signaling pathway induces a high bone mass phenotype in mice. However, clinical observations have shown that drug or genetic mediated improvement of bone mass might be associated to alterations to bone ex- tracellular matrix (ECM) properties, leading to bone fragility. Hence, in this study we propose to characterize the physical, chemical and biomechanical properties of mature bone ECM of germline NPY-Y1R knockout (Y1R−/−) mice, and compare to their wild-type (WT) littermates. Our results demonstrated that the high bone mass phenotype observed in Y1R−/− mice involves alterations in Y1R−/− bone ECM ul- trastructure, as a result of accelerated deposition of organic and mineral fractions. In addition, Y1R−/− bone ECM displays enhanced matrix maturation characterized by greater number of mature/highly packed collagen fibers without pathological accumulation of immature/mature collagen crosslinks nor compromise of mineral crystallinity. These unique features of Y1R−/− bone ECM improved the biochemical properties of Y1R−/− bones, reflected by mechanically robust bones with diminished propensity to fracture, contributing to greater bone strength. These findings support the future usage of drugs targeting Y1R signaling as a promising therapeutic strategy to treat bone loss-related pathologies.
Genetic and pharmacological functional studies have provided evidence that the lack of Neuropeptide Y-Y1 receptor (Y1R) signaling pathway induces a high bone mass phenotype in mice. However, clinical observations have shown that drug or genetic mediated improvement of bone mass might be associated to alterations to bone ex- tracellular matrix (ECM) properties, leading to bone fragility. Hence, in this study we propose to characterize the physical, chemical and biomechanical properties of mature bone ECM of germline NPY-Y1R knockout (Y1R−/−) mice, and compare to their wild-type (WT) littermates. Our results demonstrated that the high bone mass phenotype observed in Y1R−/− mice involves alterations in Y1R−/− bone ECM ul- trastructure, as a result of accelerated deposition of organic and mineral fractions. In addition, Y1R−/− bone ECM displays enhanced matrix maturation characterized by greater number of mature/highly packed collagen fibers without pathological accumulation of immature/mature collagen crosslinks nor compromise of mineral crystallinity. These unique features of Y1R−/− bone ECM improved the biochemical properties of Y1R−/− bones, reflected by mechanically robust bones with diminished propensity to fracture, contributing to greater bone strength. These findings support the future usage of drugs targeting Y1R signaling as a promising therapeutic strategy to treat bone loss-related pathologies.