The lack of neuropeptide Y‐Y ₁ receptor signaling modulates the chemical and mechanical properties of bone matrix

Abstract

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 extracellular 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 ultrastructure, 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.

The Role of NPY in the Regulation of Bone Metabolism

“…It has been observed that BMSC migration and VEGF expression were upregulated after NPY treatment ( 45 ) and increased levels of VEGF stimulate angiogenesis and osteoblastic differentiation of BMSCs ( 59 ). Besides, Y1R signaling disruption is responsible for enhancing the deposition and maturity of collagen and mineral hydroxyapatite layers in the skeletal muscle, and bone mechanical property was furthered improved ( 60 ) ( Figure 1 ).…”

Skeleton interoception regulates bone and fat metabolism through hypothalamic neuroendocrine NPY

“…Conversely, bone mass increased significantly in NPY knockout mice ( Baldock et al, 2009 ). Moreover, bone mass increased significantly in NPY Y1R knockout mice and wild-type (WT) mice treated with Y1R inhibitor because Y1R is expressed in the osteoblasts ( Brothers and Wahlestedt, 2010 ; Sousa et al, 2020 ). Importantly, embryonic stem cells accelerated adipogenesis induced by NPY system activation, which is consistent with our previous observation ( Han et al, 2012 ; Hu et al, 2020 ).…”

Early treadmill running delays rotator cuff healing via Neuropeptide Y mediated inactivation of the Wnt/β-catenin signaling

“…Consistent with prior observations, our immunochemistry results showed that Y1R was widely present at the healing site of RC. Moreover, loss of Y1R has been found to induce a high bone mass phenotype with increased deposition of mineral and extracellular matrix [ 33 ]. Sousa DM et al.…”