neuropeptide-y and Osteoporosis--Postmenopausal

Postmenopausal osteoporosis (PMO) is often accompanied by neuroendocrine changes in the hypothalamus, which closely associates with the microbial diversity, community composition, and intestinal metabolites of gut microbiota (GM). With the emerging role of GM in bone metabolism, a potential neuroendocrine signal neuropeptide Y (NPY) mediated brain-gut-bone axis has come to light. Herein, it is reported that exogenous overexpression of NPY reduced bone formation, damaged bone microstructure, and up-regulated the expressions of pyroptosis-related proteins in subchondral cancellous bone in ovariectomized (OVX) rats, but Y1 receptor antagonist (Y1Ra) reversed these changes. In addition, it is found that exogenous overexpression of NPY aggravated colonic inflammation, impaired intestinal barrier integrity, enhanced intestinal permeability, and increased serum lipopolysaccharide (LPS) in OVX rats, and Y1Ra also reversed these changes. Most importantly, NPY and Y1Ra modulated the microbial diversity and changed the community composition of GM in OVX rats, and thereby affecting the metabolites of GM (e.g., LPS) entering the blood circulation. Moreover, fecal microbiota transplantation further testified the effect of NPY-mediated GM changes on bone. In vitro, LPS induced pyroptosis, reduced viability, and inhibited differentiation of osteoblasts. The study demonstrated the existence of NPY-mediated brain-gut-bone axis and it might be a novel emerging target to treat PMO.

Topics: Animals; Female; Gastrointestinal Microbiome; Humans; Hypothalamus; Lipopolysaccharides; Neuropeptide Y; Osteoporosis, Postmenopausal; Rats

Estrogen deficiency is the main factor underlying postmenopausal osteoporosis. A large number of neuropeptides, which regulate skeletal metabolism, potentially represent a regulatory pathway for the pathogenesis of osteoporosis. The aim of this study was to explore factors involved in the regulation of bone-related neuropeptides and their association with estrogen deficiency and bone metabolism. Thirty adult female Sprague-Dawley (SD) rats were randomly divided into a control group with sham surgery (n = 15) and an ovariectomy group with bilateral oophorectomy (n = 15). After 16 weeks, serum estrogen was reduced,CTX-1 was increased and P1NP was not significantly affected in the ovariectomy group and a model of osteoporosis was established. We then investigate the gene expression and protein levels of a range of neuropeptides and their receptors, including substance P (SP) and tachykinin receptor 1 (TACR1), calcitonin gene-related peptide (CGRP) and calcitonin receptor-like (CALCRL), vasoactive intestinal polypeptide (VIP) and receptor 1 and 2 (VPAC1, 2), neuropeptide Y (NPY) and receptor Y1 and Y2, in the brain and femora. Ovariectomy reduced TACR1, CGRP, CALCRL, NPY, NPY Y2 in the brain, but increased TACR1 and decreased SP, CALCRL, VIP, VPAC2 in the bone. Collectively, our data revealed that the pathogenesis of postmenopausal osteoporosis is associated with the regulation of SP, CGRP, VIP, and NPY. These novel results are of significant importance in the development of neuropeptides as therapeutic targets.

Topics: Animals; Brain; Calcitonin Gene-Related Peptide; Calcitonin Receptor-Like Protein; Female; Humans; Neuropeptide Y; Osteoporosis, Postmenopausal; Ovariectomy; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Substance P; Vasoactive Intestinal Peptide

Ovariectomy-induced bone loss is related to an increased deposition of osteoclasts on bone surfaces. We reported that the 36-amino-acid-long neuropeptide Y (NPY) could mobilize hematopoietic stem/progenitor cells (HSPCs) from the bone marrow to the peripheral blood by regulating HSPC maintenance factors and that mobilization of HSPCs ameliorated low bone density in an ovariectomy-induced osteoporosis mouse model by reducing the number of osteoclasts. Here, we demonstrated that new NPY peptides, recombined from the cleavage of the full-length NPY, showed better functionality for HSPC mobilization than the full-length peptide. These recombinant peptides mediated HSPC mobilization with greater efficiency by decreasing HSPC maintenance factors. Furthermore, treatment with these peptides reduced the number of osteoclasts and relieved ovariectomy-induced bone loss in mice more effectively than treatment with full-length NPY. Therefore, these results suggest that peptides recombined from full-length NPY can be used to treat osteoporosis. [BMB Reports 2017; 50(3): 138-143].

Topics: Animals; Bone Marrow; Bone Marrow Cells; Disease Models, Animal; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cells; Humans; Mice; Neuropeptide Y; Osteoclasts; Osteoporosis; Osteoporosis, Postmenopausal; Ovariectomy

To explore the relationship between the distribution of neuropeptides, cancellous bone microstructure and joint pain in postmenopausal women with osteoarthritis (OA) and osteoporosis (OP).. Cancellous bone of the femoral head was obtained at the time of hip arthroplasty from 20 postmenopausal women, 10 with OA and 10 with OP. Pain intensity was evaluated using the visual analog scale (VAS) before the operation. The microstructural parameters were measured with micro-CT and the neuropeptides of the cancellous bone were stained by an immunohistochemical method.. We observed that BV/TV, Tb.Th and Th.N values in the OP were significantly decreased compared to those in the OA. Immunohistochemical analysis revealed that the mean optical density (MOD) values for SP, CGRP, and VIP in the OA group were significantly higher than those in the OP, and the MOD value for NPY in the OA was significantly lower than that in the OP. We also observed that the MOD values for SP were positively correlated with AD, BV/TV, Tb.Th, Tb.N and Conn.D and negatively with MD, Tb.Sp and SMI in all patients. The MOD values for CGRP were positively correlated with AD, BV/TV and Tb.Th. MOD values for VIP were positively correlated with BV/TV and Tb.Th and negatively with SMI. The VAS score was correlated positively with the MOD values for SP, CGRP, VIP and negatively with NPY in all patients.. Neuropeptides play an important role in the pathogenesis of OA and OP, which may cause pain and influence the bone microstructure.

Topics: Aged; Arthralgia; Calcitonin Gene-Related Peptide; Cancellous Bone; Female; Humans; Middle Aged; Neuropeptide Y; Neuropeptides; Osteoarthritis; Osteoporosis, Postmenopausal; Pain Measurement; Pain Perception; Postmenopause; Substance P; Vasoactive Intestinal Peptide

Topics: Bone Remodeling; Bone Resorption; Humans; Leptin; Neuropeptide Y; Osteoclasts; Osteoporosis, Postmenopausal; Sympathetic Nervous System