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Fu S, Xie B, Song X. Neurological Mechanisms Exploration and Therapeutic Targets in Segmental Vitiligo Accompanied by White Hair. Pigment Cell Melanoma Res 2025; 38:e70020. [PMID: 40252009 DOI: 10.1111/pcmr.70020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 03/04/2025] [Accepted: 04/06/2025] [Indexed: 04/21/2025]
Abstract
Vitiligo is the most common skin depigmentation disease, affecting 0.1%-2% of people in the world. 3.5%-20.5% of segmental patients account for the total number of vitiligo patients. It has been clinically observed that segmental vitiligo patients are more likely to generate white hair, which may be related to neuroendocrine factors. The color of human skin and hair is affected by the number and functional status of melanocytes. Vitiligo affects patients' physical and mental health due to the shame it causes from the white patches and hair. This article reviews the underlying mechanisms of segmental vitiligo with white hair based on skin and hair follicle melanocytes. The article attempts to propose possible targets for the treatment of this disease.
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Affiliation(s)
- Shiqi Fu
- Zhejiang Chinese Medical University, Hangzhou, China
| | - Bo Xie
- Department of Dermatology, Hangzhou Third People's Hospital, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China
| | - Xiuzu Song
- Department of Dermatology, Hangzhou Third People's Hospital, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China
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Zoccali C, Vervloet MG, Evenepoel P, Massy Z, Cozzolino M, Mallamaci F, Lederer ED, Andia JC, Drueke TB. The autonomic nervous system and bone health in chronic kidney disease. Eur J Clin Invest 2025; 55:e70007. [PMID: 39985733 DOI: 10.1111/eci.70007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 01/12/2025] [Indexed: 02/24/2025]
Abstract
Besides the well-known role of hormonal factors in mineral and bone metabolism, the sympathetic nervous system participates in this regulation by inhibiting bone formation and promoting bone resorption, primarily via β-adrenergic receptors expressed on osteoblasts. Conversely, the parasympathetic system, through cholinergic signalling, inhibits osteoclast activity, promoting bone formation and maintaining skeletal homeostasis. This review presents the role of the autonomic nervous system, with particular focus on the potential role of β-blockers, especially β1-selective blockers, in modulating bone health in people with normal kidney function and those with CKD. While early studies with non-selective β-blockers like propranolol showed mixed results, recent findings in postmenopausal women suggested that β1-selective β-blockers could enhance bone density by modulating sympathetic activity. Trial emulation using large databases and eventually randomized controlled trials are needed to test the hypothesis that β-blockade can favourably impact bone disease in patients with kidney failure.
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Affiliation(s)
- Carmine Zoccali
- Renal Research Institute, New York, New York, USA
- Institute of Molecular Biology and Genetics (Biogem), Ariano Irpino, Italy
- Associazione Ipertensione Nefrologia Trapianto Renale (IPNET), Reggio di Calabria, Italy
| | - Marc G Vervloet
- Nephrology Department, Amsterdam UMC, Amsterdam, The Netherlands
| | - Pieter Evenepoel
- Department of Medicine, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Ziad Massy
- Inserm Unit 1018, Team 5, CESP, Hôpital Paul Brousse, Paris-Sud University (UPS) and Versailles Saint-Quentin-En-Yvelines University (Paris-Ile-de-France-Ouest University, UVSQ), Villejuif, France
- Association Pour l'Utilisation du Rein Artificiel Dans la région Parisienne (AURA), Paris, France
- Department of Nephrology, Ambroise Paré University Hospital, APHP, Boulogne-Billancourt, Paris, France
| | - Mario Cozzolino
- Renal Division, Department of Health Sciences, University of Milan, ASST Santi Paolo e Carlo, Milan, Italy
| | - Francesca Mallamaci
- Unità Operativa di Nefrologia e Trapianto Renale, Grande Ospedale Metropolitano, Reggio Calabria, Italy
- Clinical Epidemiology Unit of the CNR Institute of Clinical Physiology, Grande Ospedale Metropolitan, Reggio Calabria, Italy
| | - Eleanor D Lederer
- Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky, USA
- Veterans Affairs North Texas Health Care Services, Dallas, Texas, USA
- UT Southwestern Medical Center, Dallas, Texas, USA
| | - Jorge Cannata Andia
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS2040, Kidney Disease), Madrid, Spain
- Department of Medicine, Universidad de Oviedo, Oviedo, Spain
| | - Tilman B Drueke
- Inserm Unit 1018, Team 5, CESP, Hôpital Paul Brousse, Paris-Sud University (UPS), Villejuif, France
- Versailles Saint-Quentin-En-Yvelines University (Paris-Ile-de-France-Ouest University, UVSQ), Villejuif, France
- Inserm U 1038, Centre de Recherche Des Cordeliers, Paris-Cité University, Sorbonne-University, Paris, France
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Zhang J, Li J, Huang J, Xiang X, Li R, Zhai Y, Lin S, Liu W. Psychological stress disturbs bone metabolism via miR-335-3p/Fos signaling in osteoclast. eLife 2025; 13:RP95944. [PMID: 39773351 PMCID: PMC11709429 DOI: 10.7554/elife.95944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2025] Open
Abstract
It has been well validated that chronic psychological stress leads to bone loss, but the underlying mechanism remains unclarified. In this study, we established and analyzed the chronic unpredictable mild stress (CUMS) mice to investigate the miRNA-related pathogenic mechanism involved in psychological stress-induced osteoporosis. Our result found that these CUMS mice exhibited osteoporosis phenotype that is mainly attributed to the abnormal activities of osteoclasts. Subsequently, miRNA sequencing and other analysis showed that miR-335-3p, which is normally highly expressed in the brain, was significantly downregulated in the nucleus ambiguous, serum, and bone of the CUMS mice. Additionally, in vitro studies detected that miR-335-3p is important for osteoclast differentiation, with its direct targeting site in Fos. Further studies demonstrated FOS was upregulated in CUMS osteoclast, and the inhibition of FOS suppressed the accelerated osteoclastic differentiation, as well as the expression of osteoclastic genes, such as Nfatc1, Acp5, and Mmp9, in miR-335-3p-restrained osteoclasts. In conclusion, this work indicated that psychological stress may downregulate the miR-335-3p expression, which resulted in the accumulation of FOS and the upregulation of NFACT1 signaling pathway in osteoclasts, leading to its accelerated differentiation and abnormal activity. These results decipher a previously unrecognized paradigm that miRNA can act as a link between psychological stress and bone metabolism.
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Affiliation(s)
- Jiayao Zhang
- Shanghai Engineering Research Center of Tooth Restoration and Regeneration & Tongji Research Institute of Stomatology & Department of Prosthodontics, Shanghai Tongji Stomatological Hospital and Dental School, Tongji UniversityShanghaiChina
| | - Juan Li
- Shanghai Engineering Research Center of Tooth Restoration and Regeneration & Tongji Research Institute of Stomatology & Department of Prosthodontics, Shanghai Tongji Stomatological Hospital and Dental School, Tongji UniversityShanghaiChina
| | - Jiehong Huang
- Department of Neurology and Neurological Rehabilitation, Shanghai Disabled Persons' Federation Key Laboratory of Intelligent Rehabilitation Assistive Devices and Technologies, Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Medicine, Tongji UniversityShanghaiChina
| | - Xuerui Xiang
- Department of Neurology and Neurological Rehabilitation, Shanghai Disabled Persons' Federation Key Laboratory of Intelligent Rehabilitation Assistive Devices and Technologies, Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Medicine, Tongji UniversityShanghaiChina
| | - Ruoyu Li
- Department of Neurology and Neurological Rehabilitation, Shanghai Disabled Persons' Federation Key Laboratory of Intelligent Rehabilitation Assistive Devices and Technologies, Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Medicine, Tongji UniversityShanghaiChina
| | - Yun Zhai
- Shanghai Engineering Research Center of Tooth Restoration and Regeneration & Tongji Research Institute of Stomatology & Department of Prosthodontics, Shanghai Tongji Stomatological Hospital and Dental School, Tongji UniversityShanghaiChina
| | - Shuxian Lin
- Shanghai Engineering Research Center of Tooth Restoration and Regeneration & Tongji Research Institute of Stomatology & Department of Prosthodontics, Shanghai Tongji Stomatological Hospital and Dental School, Tongji UniversityShanghaiChina
| | - Weicai Liu
- Shanghai Engineering Research Center of Tooth Restoration and Regeneration & Tongji Research Institute of Stomatology & Department of Prosthodontics, Shanghai Tongji Stomatological Hospital and Dental School, Tongji UniversityShanghaiChina
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Paulini MR, Aimone M, Feldman S, Buchaim DV, Buchaim RL, Issa JPM. Relationship of Chronic Stress and Hypertension with Bone Resorption. J Funct Morphol Kinesiol 2025; 10:21. [PMID: 39846662 PMCID: PMC11755563 DOI: 10.3390/jfmk10010021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 12/18/2024] [Accepted: 12/19/2024] [Indexed: 01/24/2025] Open
Abstract
Background/Objectives: Chronic exposure to stress has been considered a risk factor for hypertension, which is also associated with increased bone resorption. This review aimed to investigate the effect of acute and chronic stress, associated with hypertension, on the skeletal system. Methods: A comprehensive search was conducted across multiple databases, focusing on peer-reviewed articles published in English. We include experimental, clinical, and peer-reviewed studies focused on the relationship between stress, hypertension, and bone resorption. Searches were conducted in MEDLINE via PubMed, Embase and Scopus, with the last search completed on 10 September 2024. Results: The main topics include situations that favor bone loss, such as psychological stress, which can lead to osteoporotic fractures through immunological and endocrine mechanisms. The relationship between psychological stress and loss of bone density, as in osteoporosis, occurs due to the reduction in the number of osteoblasts and loss in the balance between physiological formation/resorption. Conclusions: Chronic stress significantly affects cardiovascular health and bone resorption. This narrative review study highlights the vulnerability of the skeletal system, along with the cardiovascular system, to prolonged stress, emphasizing the need for multidisciplinary strategies in preventing stress-related conditions. Effective stress management can help reduce the risks of cardiovascular disease and bone resorption, emphasizing their role in comprehensive health care.
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Affiliation(s)
- Marina Ribeiro Paulini
- Department of Basic and Oral Biology, School of Dentistry of Ribeirão Preto, University of São Paulo (FORP-USP), Ribeirão Preto 14040-904, Brazil;
| | - Mariangeles Aimone
- LABOATEM, Laboratory of Ostearticular Biology and Tissue Engineering, School of Medicine, Rosario S2002, Argentina; (M.A.); (S.F.)
| | - Sara Feldman
- LABOATEM, Laboratory of Ostearticular Biology and Tissue Engineering, School of Medicine, Rosario S2002, Argentina; (M.A.); (S.F.)
- Research Council, National Rosario University (CIUNR-CONICET), Rosario S2002, Argentina
| | - Daniela Vieira Buchaim
- Medical School, University Center of Adamantina (FAI), Adamantina 17800-000, Brazil;
- Graduate Program in Anatomy of Domestic and Wild Animals, Faculty of Veterinary Medicine and Animal Science, University of São Paulo (FMVZ/USP), Sao Paulo 05508-270, Brazil;
- Center for the Study of Venoms and Venomous Animals, São Paulo State University (CEVAP/UNESP), Botucatu 18619-002, Brazil
| | - Rogerio Leone Buchaim
- Graduate Program in Anatomy of Domestic and Wild Animals, Faculty of Veterinary Medicine and Animal Science, University of São Paulo (FMVZ/USP), Sao Paulo 05508-270, Brazil;
- Center for the Study of Venoms and Venomous Animals, São Paulo State University (CEVAP/UNESP), Botucatu 18619-002, Brazil
- Department of Biological Sciences, School of Dentistry of Bauru, University of São Paulo (FOB-USP), Bauru 17012-901, Brazil
| | - João Paulo Mardegan Issa
- Department of Basic and Oral Biology, School of Dentistry of Ribeirão Preto, University of São Paulo (FORP-USP), Ribeirão Preto 14040-904, Brazil;
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Pierre-Jerome C. The peripheral nervous system: peripheral neuropathies in the diabetic foot. MYOPATHIES AND TENDINOPATHIES OF THE DIABETIC FOOT 2025:451-482. [DOI: 10.1016/b978-0-443-13328-2.00022-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Guo B, Zhu Y, Lu S, Chen X, Ren Z, Liu Y, Luo H, Wang C, Yang X, Zhu J. Targeting MCH Neuroendocrine Circuit in Lateral Hypothalamus to Protect Against Skeletal Senescence. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2309951. [PMID: 39320347 DOI: 10.1002/advs.202309951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 08/28/2024] [Indexed: 09/26/2024]
Abstract
Neuroendocrine regulation is essential for maintaining metabolic homeostasis. However, whether neuroendocrine pathway influence bone metabolism and skeletal senescence is unelucidated. Here, a central neuroendocrine circuit is identified that directly controls osteogenesis. Using virus based tracing, this study is identified that melanin concentrating hormone (MCH) expressing neurons in the lateral hypothalamus (LH) are connected to the bone. Chemogenetic activation of MCH neurons in the LH induces osteogenesis, whereas inhibiting these neurons reduces osteogenesis. Meanwhile, MCH is released into the circulation upon chemogenetic activation of these neurons. Single cell sequencing reveals that blocking MCH neurons in the LH diminishes osteogenic differentiation of bone marrow stromal cells (BMSCs) and induces senescence. Mechanistically, MCH promotes BMSC differentiation by activating MCHR1 via PKA signaling, and activating MCHR1 by MCH agonists attenuate skeletal senescence in mice. By elucidating a brain-bone connection that autonomously enhances osteogenesis, these findings uncover the neuroendocrinological mechanisms governing bone mass regulation and protect against skeletal senescence.
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Affiliation(s)
- Bin Guo
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yong Zhu
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Shuai Lu
- Department of Orthopedic Trauma, Beijing Jishuitan Hospital, Capital Medical University, Beijing, 100035, China
- Beijing Research Institute of Traumatology and Orthopaedics, Beijing, 100035, China
| | - Xiangming Chen
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Zhuoqun Ren
- Xiangya School of Medicine, Central South University, Changsha, 410008, China
| | - Yuqi Liu
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Hao Luo
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Chao Wang
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Xucheng Yang
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Jianxi Zhu
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, 410008, China
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Hunan, 410008, China
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Liu H, Wu J, Wu H, Wang T, Zhou H, Liu M. Autologous ADSCs with exogenous NPY promotes fracture healing in ovariectomized rats. Heliyon 2024; 10:e38297. [PMID: 39421363 PMCID: PMC11483299 DOI: 10.1016/j.heliyon.2024.e38297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Revised: 09/09/2024] [Accepted: 09/20/2024] [Indexed: 10/19/2024] Open
Abstract
Objective To evaluate the role of autologous adipose-derived stem cells (ADSCs) with exogenous neuropeptide Y (NPY) on osteoporotic fracture healing. Methods We established a fracture healing model in ovariectomized rats of osteoporosis. Autologous ADSCs, isolated from rats' subcutaneous adipose tissue, with exogenous NPY were transplanted into the fracture site four times a week. The fracture healing was observiked with X-ray diagnostic techniques, and the rats' tibias were taken out for section-staining and micro-CT scanning 3 and 6 weeks after fracture. Next, we explored the underlying mechanism by which the transplantation contributed to fracture healing. Results Co-culture and co-transplantation of ADSCs with NPY could stimulate the osteoporotic fracture healing. NPY may promote the osteogenic differentiation of ADSCs through Y1 receptor. Conclusion This result provides a platform for the development of novel therapies for bone regeneration with endogenous ADSCs.
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Affiliation(s)
- Hong Liu
- Department of Nutrition, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, PR China
| | - Jiaoyang Wu
- Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, PR China
| | - Huixuan Wu
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second XiangYa Hospital of Central South University, Changsha, Hunan 410011, PR China
| | - Ting Wang
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second XiangYa Hospital of Central South University, Changsha, Hunan 410011, PR China
| | - Houde Zhou
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second XiangYa Hospital of Central South University, Changsha, Hunan 410011, PR China
| | - Min Liu
- Department of Nutrition, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, PR China
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Szeliga A, Grymowicz M, Kostrzak A, Smolarczyk R, Bala G, Smolarczyk K, Meczekalski B, Suchta K. Bone: A Neglected Endocrine Organ? J Clin Med 2024; 13:3889. [PMID: 38999458 PMCID: PMC11242793 DOI: 10.3390/jcm13133889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 06/26/2024] [Accepted: 06/30/2024] [Indexed: 07/14/2024] Open
Abstract
Bone has traditionally been viewed in the context of its structural contribution to the human body. Foremost providing necessary support for mobility, its roles in supporting calcium homeostasis and blood cell production are often afterthoughts. Recent research has further shed light on the ever-multifaceted role of bone and its importance not only for structure, but also as a complex endocrine organ producing hormones responsible for the autoregulation of bone metabolism. Osteocalcin is one of the most important substances produced in bone tissue. Osteocalcin in circulation increases insulin secretion and sensitivity, lowers blood glucose, and decreases visceral adipose tissue. In males, it has also been shown to enhance testosterone production by the testes. Neuropeptide Y is produced by various cell types including osteocytes and osteoblasts, and there is evidence suggesting that peripheral NPY is important for regulation of bone formation. Hormonal disorders are often associated with abnormal levels of bone turnover markers. These include commonly used bone formation markers (bone alkaline phosphatase, osteocalcin, and procollagen I N-propeptide) and commonly used resorption markers (serum C-telopeptides of type I collagen, urinary N-telopeptides of type I collagen, and tartrate-resistant acid phosphatase type 5b). Bone, however, is not exclusively comprised of osseous tissue. Bone marrow adipose tissue, an endocrine organ often compared to visceral adipose tissue, is found between trabecula in the bone cortex. It secretes a diverse range of hormones, lipid species, cytokines, and other factors to exert diverse local and systemic effects.
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Affiliation(s)
- Anna Szeliga
- Department of Gynecological Endocrinology, Poznan University of Medical Sciences, 60-535 Poznan, Poland
| | - Monika Grymowicz
- Department of Gynecological Endocrinology, Warsaw Medical University, 00-315 Warsaw, Poland
| | - Anna Kostrzak
- Department of Gynecological Endocrinology, Poznan University of Medical Sciences, 60-535 Poznan, Poland
| | - Roman Smolarczyk
- Department of Gynecological Endocrinology, Warsaw Medical University, 00-315 Warsaw, Poland
| | - Gregory Bala
- UCD School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland
| | | | - Blazej Meczekalski
- Department of Gynecological Endocrinology, Poznan University of Medical Sciences, 60-535 Poznan, Poland
| | - Katarzyna Suchta
- Department of Gynecological Endocrinology, Warsaw Medical University, 00-315 Warsaw, Poland
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Li J, Zhang Z, Tang J, Hou Z, Li L, Li B. Emerging roles of nerve-bone axis in modulating skeletal system. Med Res Rev 2024; 44:1867-1903. [PMID: 38421080 DOI: 10.1002/med.22031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 01/25/2024] [Accepted: 02/16/2024] [Indexed: 03/02/2024]
Abstract
Over the past decades, emerging evidence in the literature has demonstrated that the innervation of bone is a crucial modulator for skeletal physiology and pathophysiology. The nerve-bone axis sparked extensive preclinical and clinical investigations aimed at elucidating the contribution of nerve-bone crosstalks to skeleton metabolism, homeostasis, and injury repair through the perspective of skeletal neurobiology. To date, peripheral nerves have been widely reported to mediate bone growth and development and fracture healing via the secretion of neurotransmitters, neuropeptides, axon guidance factors, and neurotrophins. Relevant studies have further identified several critical neural pathways that stimulate profound alterations in bone cell biology, revealing a complex interplay between the skeleton and nerve systems. In addition, inspired by nerve-bone crosstalk, novel drug delivery systems and bioactive materials have been developed to emulate and facilitate the process of natural bone repair through neuromodulation, eventually boosting osteogenesis for ideal skeletal tissue regeneration. Overall, this work aims to review the novel research findings that contribute to deepening the current understanding of the nerve-bone axis, bringing forth some schemas that can be translated into the clinical scenario to highlight the critical roles of neuromodulation in the skeletal system.
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Affiliation(s)
- Jingya Li
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Zhuoyuan Zhang
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jinru Tang
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Zeyu Hou
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Longjiang Li
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Bo Li
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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Shi H, Chen M. The brain-bone axis: unraveling the complex interplay between the central nervous system and skeletal metabolism. Eur J Med Res 2024; 29:317. [PMID: 38849920 PMCID: PMC11161955 DOI: 10.1186/s40001-024-01918-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Accepted: 06/03/2024] [Indexed: 06/09/2024] Open
Abstract
The brain-bone axis has emerged as a captivating field of research, unveiling the intricate bidirectional communication between the central nervous system (CNS) and skeletal metabolism. This comprehensive review delves into the current state of knowledge surrounding the brain-bone axis, exploring the complex mechanisms, key players, and potential clinical implications of this fascinating area of study. The review discusses the neural regulation of bone metabolism, highlighting the roles of the sympathetic nervous system, hypothalamic neuropeptides, and neurotransmitters in modulating bone remodeling. In addition, it examines the influence of bone-derived factors, such as osteocalcin and fibroblast growth factor 23, on brain function and behavior. The therapeutic potential of targeting the brain-bone axis in the context of skeletal and neurological disorders is also explored. By unraveling the complex interplay between the CNS and skeletal metabolism, this review aims to provide a comprehensive resource for researchers, clinicians, and students interested in the brain-bone axis and its implications for human health and disease.
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Affiliation(s)
- Haojun Shi
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, Macau SAR, China
| | - Min Chen
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, Macau SAR, China.
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11
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Kumari R, Pascalau R, Wang H, Bajpayi S, Yurgel M, Quansah K, Hattar S, Tampakakis E, Kuruvilla R. Sympathetic NPY controls glucose homeostasis, cold tolerance, and cardiovascular functions in mice. Cell Rep 2024; 43:113674. [PMID: 38236776 PMCID: PMC10951981 DOI: 10.1016/j.celrep.2024.113674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 11/17/2023] [Accepted: 01/01/2024] [Indexed: 01/30/2024] Open
Abstract
Neuropeptide Y (NPY) is best known for its effects in the brain as an orexigenic and anxiolytic agent and in reducing energy expenditure. NPY is also co-expressed with norepinephrine (NE) in sympathetic neurons. Although NPY is generally considered to modulate noradrenergic responses, its specific roles in autonomic physiology remain under-appreciated. Here, we show that sympathetic-derived NPY is essential for metabolic and cardiovascular regulation in mice. NPY and NE are co-expressed in 90% of prevertebral sympathetic neurons and only 43% of paravertebral neurons. NPY-expressing neurons primarily innervate blood vessels in peripheral organs. Sympathetic-specific NPY deletion elicits pronounced metabolic and cardiovascular defects in mice, including reductions in insulin secretion, glucose tolerance, cold tolerance, and pupil size and elevated heart rate, while notably, however, basal blood pressure was unchanged. These findings provide insight into target tissue-specific functions of NPY derived from sympathetic neurons and imply its potential involvement in metabolic and cardiovascular diseases.
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Affiliation(s)
- Raniki Kumari
- Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Raluca Pascalau
- Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Hui Wang
- Section on Light and Circadian Rhythms, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA
| | - Sheetal Bajpayi
- Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Maria Yurgel
- Section on Light and Circadian Rhythms, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA
| | - Kwaku Quansah
- Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA; Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Samer Hattar
- Section on Light and Circadian Rhythms, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA
| | - Emmanouil Tampakakis
- Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Rejji Kuruvilla
- Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA.
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Zhao Y, Peng X, Wang Q, Zhang Z, Wang L, Xu Y, Yang H, Bai J, Geng D. Crosstalk Between the Neuroendocrine System and Bone Homeostasis. Endocr Rev 2024; 45:95-124. [PMID: 37459436 DOI: 10.1210/endrev/bnad025] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Indexed: 01/05/2024]
Abstract
The homeostasis of bone microenvironment is the foundation of bone health and comprises 2 concerted events: bone formation by osteoblasts and bone resorption by osteoclasts. In the early 21st century, leptin, an adipocytes-derived hormone, was found to affect bone homeostasis through hypothalamic relay and the sympathetic nervous system, involving neurotransmitters like serotonin and norepinephrine. This discovery has provided a new perspective regarding the synergistic effects of endocrine and nervous systems on skeletal homeostasis. Since then, more studies have been conducted, gradually uncovering the complex neuroendocrine regulation underlying bone homeostasis. Intriguingly, bone is also considered as an endocrine organ that can produce regulatory factors that in turn exert effects on neuroendocrine activities. After decades of exploration into bone regulation mechanisms, separate bioactive factors have been extensively investigated, whereas few studies have systematically shown a global view of bone homeostasis regulation. Therefore, we summarized the previously studied regulatory patterns from the nervous system and endocrine system to bone. This review will provide readers with a panoramic view of the intimate relationship between the neuroendocrine system and bone, compensating for the current understanding of the regulation patterns of bone homeostasis, and probably developing new therapeutic strategies for its related disorders.
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Affiliation(s)
- Yuhu Zhao
- Department of Orthopedics, The First Affiliated Hospital of Soochow University; Orthopedics Institute, Medical College, Soochow University, Suzhou, Jiangsu 215006, China
| | - Xiaole Peng
- Department of Orthopedics, The First Affiliated Hospital of Soochow University; Orthopedics Institute, Medical College, Soochow University, Suzhou, Jiangsu 215006, China
| | - Qing Wang
- Department of Orthopedics, The First Affiliated Hospital of Soochow University; Orthopedics Institute, Medical College, Soochow University, Suzhou, Jiangsu 215006, China
| | - Zhiyu Zhang
- Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China
| | - Liangliang Wang
- Department of Orthopedics, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213000, China
| | - Yaozeng Xu
- Department of Orthopedics, The First Affiliated Hospital of Soochow University; Orthopedics Institute, Medical College, Soochow University, Suzhou, Jiangsu 215006, China
| | - Huilin Yang
- Department of Orthopedics, The First Affiliated Hospital of Soochow University; Orthopedics Institute, Medical College, Soochow University, Suzhou, Jiangsu 215006, China
| | - Jiaxiang Bai
- Department of Orthopedics, The First Affiliated Hospital of Soochow University; Orthopedics Institute, Medical College, Soochow University, Suzhou, Jiangsu 215006, China
- Department of Orthopedics, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230022, China
| | - Dechun Geng
- Department of Orthopedics, The First Affiliated Hospital of Soochow University; Orthopedics Institute, Medical College, Soochow University, Suzhou, Jiangsu 215006, China
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13
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Sun W, Ye B, Chen S, Zeng L, Lu H, Wan Y, Gao Q, Chen K, Qu Y, Wu B, Lv X, Guo X. Neuro-bone tissue engineering: emerging mechanisms, potential strategies, and current challenges. Bone Res 2023; 11:65. [PMID: 38123549 PMCID: PMC10733346 DOI: 10.1038/s41413-023-00302-8] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 10/08/2023] [Accepted: 10/31/2023] [Indexed: 12/23/2023] Open
Abstract
The skeleton is a highly innervated organ in which nerve fibers interact with various skeletal cells. Peripheral nerve endings release neurogenic factors and sense skeletal signals, which mediate bone metabolism and skeletal pain. In recent years, bone tissue engineering has increasingly focused on the effects of the nervous system on bone regeneration. Simultaneous regeneration of bone and nerves through the use of materials or by the enhancement of endogenous neurogenic repair signals has been proven to promote functional bone regeneration. Additionally, emerging information on the mechanisms of skeletal interoception and the central nervous system regulation of bone homeostasis provide an opportunity for advancing biomaterials. However, comprehensive reviews of this topic are lacking. Therefore, this review provides an overview of the relationship between nerves and bone regeneration, focusing on tissue engineering applications. We discuss novel regulatory mechanisms and explore innovative approaches based on nerve-bone interactions for bone regeneration. Finally, the challenges and future prospects of this field are briefly discussed.
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Affiliation(s)
- Wenzhe Sun
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Bing Ye
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Siyue Chen
- School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Lian Zeng
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Hongwei Lu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Yizhou Wan
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Qing Gao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Kaifang Chen
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Yanzhen Qu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Bin Wu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Xiao Lv
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
| | - Xiaodong Guo
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
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14
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Kumari R, Pascalau R, Wang H, Bajpayi S, Yurgel M, Quansah K, Hattar S, Tampakakis E, Kuruvilla R. Sympathetic NPY controls glucose homeostasis, cold tolerance, and cardiovascular functions in mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.07.24.550381. [PMID: 37546870 PMCID: PMC10402010 DOI: 10.1101/2023.07.24.550381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/08/2023]
Abstract
Neuropeptide Y (NPY) is best known for its effects in the brain as an orexigenic and anxiolytic agent and in reducing energy expenditure. NPY is also co-expressed with Norepinephrine (NE) in sympathetic neurons. Although NPY is generally considered to modulate noradrenergic responses, its specific roles in autonomic physiology remain under-appreciated. Here, we show that sympathetic-derived NPY is essential for metabolic and cardiovascular regulation in mice. NPY and NE are co-expressed in 90% of prevertebral sympathetic neurons and only 43% of paravertebral neurons. NPY-expressing neurons primarily innervate blood vessels in peripheral organs. Sympathetic-specific deletion of NPY elicits pronounced metabolic and cardiovascular defects in mice, including reductions in insulin secretion, glucose tolerance, cold tolerance, pupil size, and an elevation in heart rate, while notably, however, basal blood pressure was unchanged. These findings provide new knowledge about target tissue-specific functions of NPY derived from sympathetic neurons and imply its potential involvement in metabolic and cardiovascular diseases.
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Affiliation(s)
- Raniki Kumari
- Department of Biology, Johns Hopkins University, Baltimore, Maryland, 21218, USA
| | - Raluca Pascalau
- Department of Biology, Johns Hopkins University, Baltimore, Maryland, 21218, USA
| | - Hui Wang
- Section on Light and Circadian Rhythms, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, 20892, USA
| | - Sheetal Bajpayi
- Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, Maryland, 21205, USA
| | - Maria Yurgel
- Section on Light and Circadian Rhythms, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, 20892, USA
| | - Kwaku Quansah
- Department of Biology, Johns Hopkins University, Baltimore, Maryland, 21218, USA
- Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, Maryland, 21205, USA
| | - Samer Hattar
- Section on Light and Circadian Rhythms, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, 20892, USA
| | - Emmanouil Tampakakis
- Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, Maryland, 21205, USA
| | - Rejji Kuruvilla
- Department of Biology, Johns Hopkins University, Baltimore, Maryland, 21218, USA
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15
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Liu W, Chen W, Xie M, Chen C, Shao Z, Zhang Y, Zhao H, Song Q, Hu H, Xing X, Cai X, Deng X, Li X, Wang P, Liu G, Xiong L, Lv X, Zhang Y. Traumatic brain injury stimulates sympathetic tone-mediated bone marrow myelopoiesis to favor fracture healing. Signal Transduct Target Ther 2023; 8:260. [PMID: 37402714 DOI: 10.1038/s41392-023-01457-w] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 04/08/2023] [Accepted: 04/25/2023] [Indexed: 07/06/2023] Open
Abstract
Traumatic brain injury (TBI) accelerates fracture healing, but the underlying mechanism remains largely unknown. Accumulating evidence indicates that the central nervous system (CNS) plays a pivotal role in regulating immune system and skeletal homeostasis. However, the impact of CNS injury on hematopoiesis commitment was overlooked. Here, we found that the dramatically elevated sympathetic tone accompanied with TBI-accelerated fracture healing; chemical sympathectomy blocks TBI-induced fracture healing. TBI-induced hypersensitivity of adrenergic signaling promotes the proliferation of bone marrow hematopoietic stem cells (HSCs) and swiftly skews HSCs toward anti-inflammation myeloid cells within 14 days, which favor fracture healing. Knockout of β3- or β2-adrenergic receptor (AR) eliminate TBI-mediated anti-inflammation macrophage expansion and TBI-accelerated fracture healing. RNA sequencing of bone marrow cells revealed that Adrb2 and Adrb3 maintain proliferation and commitment of immune cells. Importantly, flow cytometry confirmed that deletion of β2-AR inhibits M2 polarization of macrophages at 7th day and 14th day; and TBI-induced HSCs proliferation was impaired in β3-AR knockout mice. Moreover, β3- and β2-AR agonists synergistically promote infiltration of M2 macrophages in callus and accelerate bone healing process. Thus, we conclude that TBI accelerates bone formation during early stage of fracture healing process by shaping the anti-inflammation environment in the bone marrow. These results implicate that the adrenergic signals could serve as potential targets for fracture management.
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Affiliation(s)
- Weijian Liu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Department of Orthopaedic Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, 050051, China
| | - Wei Chen
- Department of Orthopaedic Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, 050051, China
| | - Mao Xie
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Chao Chen
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Zengwu Shao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yiran Zhang
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Haiyue Zhao
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Qingcheng Song
- Department of Orthopaedic Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, 050051, China
- NHC Key Laboratory of Intelligent Orthopeadic Equipment, Third Hospital of Hebei Medical University, Shijiazhuang, 050051, China
- Animal Center of Hebei Ex & In vivo Biotechnology, Shijiazhuang, 050051, China
| | - Hongzhi Hu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Department of Orthopaedic Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, 050051, China
| | - Xin Xing
- Department of Orthopaedic Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, 050051, China
- NHC Key Laboratory of Intelligent Orthopeadic Equipment, Third Hospital of Hebei Medical University, Shijiazhuang, 050051, China
| | - Xianyi Cai
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xiangtian Deng
- Department of Orthopaedic Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, 050051, China
- NHC Key Laboratory of Intelligent Orthopeadic Equipment, Third Hospital of Hebei Medical University, Shijiazhuang, 050051, China
| | - Xinyan Li
- Department of Physiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Peng Wang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Guohui Liu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Liming Xiong
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Xiao Lv
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Yingze Zhang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Department of Orthopaedic Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, 050051, China.
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16
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Zhang L, Liu N, Shao J, Gao D, Liu Y, Zhao Y, Han C, Chen D, Wang L, Lu WW, Yang F. Bidirectional control of parathyroid hormone and bone mass by subfornical organ. Neuron 2023; 111:1914-1932.e6. [PMID: 37084721 DOI: 10.1016/j.neuron.2023.03.030] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 11/02/2022] [Accepted: 03/23/2023] [Indexed: 04/23/2023]
Abstract
Parathyroid hormone (PTH) is one of the most important hormones for bone turnover and calcium homeostasis. It is unclear how the central nervous system regulates PTH. The subfornical organ (SFO) lies above the third ventricle and modulates body fluid homeostasis. Through retrograde tracing, electrophysiology, and in vivo calcium imaging, we identified the SFO as an important brain nucleus that responds to serum PTH changes in mice. Chemogenetic stimulation of GABAergic neurons in SFO induces decreased serum PTH followed by a decrease in trabecular bone mass. Conversely, stimulation of glutamatergic neurons in the SFO promoted serum PTH and bone mass. Moreover, we found that the blockage of different PTH receptors in the SFO affects peripheral PTH levels and the PTH's response to calcium stimulation. Furthermore, we identified a GABAergic projection from the SFO to the paraventricular nucleus, which modulates PTH and bone mass. These findings advance our understanding of the central neural regulation of PTH at cellular and circuit level.
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Affiliation(s)
- Lu Zhang
- The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China; Department of Orthopaedics and Traumatology, The University of Hong Kong, Hong Kong SAR, China
| | - Nian Liu
- The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China; Department of Orthopaedics and Traumatology, The University of Hong Kong, Hong Kong SAR, China; Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Jie Shao
- The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Dashuang Gao
- The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Yunhui Liu
- The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Yingzi Zhao
- The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Chuanliang Han
- The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Di Chen
- Faculty of Pharmaceutical Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Liping Wang
- The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China; The Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, Shenzhen, Guangdong, China; CAS Key Laboratory of Brain Connectome and Manipulation, Shenzhen, Guangdong, China; Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, Guangdong, China
| | - William Weijia Lu
- Department of Orthopaedics and Traumatology, The University of Hong Kong, Hong Kong SAR, China; Faculty of Pharmaceutical Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
| | - Fan Yang
- The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China; The Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, Shenzhen, Guangdong, China; CAS Key Laboratory of Brain Connectome and Manipulation, Shenzhen, Guangdong, China; Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, Guangdong, China.
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17
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Tschaffon-Müller MEA, Kempter E, Steppe L, Kupfer S, Kuhn MR, Gebhard F, Pankratz C, Kalbitz M, Schütze K, Gündel H, Kaleck N, Strauß G, Vacher J, Ichinose H, Weimer K, Ignatius A, Haffner-Luntzer M, Reber SO. Neutrophil-derived catecholamines mediate negative stress effects on bone. Nat Commun 2023; 14:3262. [PMID: 37277336 DOI: 10.1038/s41467-023-38616-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 05/09/2023] [Indexed: 06/07/2023] Open
Abstract
Mental traumatization is associated with long-bone growth retardation, osteoporosis and increased fracture risk. We revealed earlier that mental trauma disturbs cartilage-to-bone transition during bone growth and repair in mice. Trauma increased tyrosine hydroxylase-expressing neutrophils in bone marrow and fracture callus. Here we show that tyrosine hydroxylase expression in the fracture hematoma of patients correlates positively with acknowledged stress, depression, and pain scores as well as individual ratings of healing-impairment and pain-perception post-fracture. Moreover, mice lacking tyrosine hydroxylase in myeloid cells are protected from chronic psychosocial stress-induced disturbance of bone growth and healing. Chondrocyte-specific β2-adrenoceptor-deficient mice are also protected from stress-induced bone growth retardation. In summary, our preclinical data identify locally secreted catecholamines in concert with β2-adrenoceptor signalling in chondrocytes as mediators of negative stress effects on bone growth and repair. Given our clinical data, these mechanistic insights seem to be of strong translational relevance.
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Affiliation(s)
| | - Elena Kempter
- Laboratory for Molecular Psychosomatics, Department of Psychosomatic Medicine and Psychotherapy, Ulm University Medical Center, Ulm, Germany
| | - Lena Steppe
- Institute of Orthopaedic Research and Biomechanics, Ulm University Medical Center, Ulm, Germany
| | - Sandra Kupfer
- Laboratory for Molecular Psychosomatics, Department of Psychosomatic Medicine and Psychotherapy, Ulm University Medical Center, Ulm, Germany
| | - Melanie R Kuhn
- Institute of Orthopaedic Research and Biomechanics, Ulm University Medical Center, Ulm, Germany
| | - Florian Gebhard
- Department of Orthopedic Trauma, Hand-, Plastic- and Reconstructive Surgery, Ulm University Medical Center, Ulm, Germany
| | - Carlos Pankratz
- Department of Orthopedic Trauma, Hand-, Plastic- and Reconstructive Surgery, Ulm University Medical Center, Ulm, Germany
| | - Miriam Kalbitz
- Department of Orthopedic Trauma, Hand-, Plastic- and Reconstructive Surgery, Ulm University Medical Center, Ulm, Germany
- Department of Trauma and Orthopedic Surgery, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Konrad Schütze
- Department of Orthopedic Trauma, Hand-, Plastic- and Reconstructive Surgery, Ulm University Medical Center, Ulm, Germany
| | - Harald Gündel
- Department of Psychosomatic Medicine and Psychotherapy, Ulm University Medical Center, Ulm, Germany
| | - Nele Kaleck
- Department of Psychosomatic Medicine and Psychotherapy, Ulm University Medical Center, Ulm, Germany
| | - Gudrun Strauß
- Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany
| | - Jean Vacher
- Department of Medicine, Institut de Recherches Cliniques de Montréal, Montréal, QC, Canada
- Institut de Recherche Cliniques de Montréal, Department of Medicine, Université de Montréal, H2W 1R7, Montréal, QC, Canada
| | - Hiroshi Ichinose
- School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan
| | - Katja Weimer
- Department of Psychosomatic Medicine and Psychotherapy, Ulm University Medical Center, Ulm, Germany
| | - Anita Ignatius
- Institute of Orthopaedic Research and Biomechanics, Ulm University Medical Center, Ulm, Germany
| | - Melanie Haffner-Luntzer
- Institute of Orthopaedic Research and Biomechanics, Ulm University Medical Center, Ulm, Germany
| | - Stefan O Reber
- Laboratory for Molecular Psychosomatics, Department of Psychosomatic Medicine and Psychotherapy, Ulm University Medical Center, Ulm, Germany.
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18
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Yang M, Li XL, Zhang YT, Deng YW, Jiao Y. miR-10a-3p Participates in Nacre Formation in the Pearl Oyster Pinctada fucata martensii by Targeting NPY. MARINE BIOTECHNOLOGY (NEW YORK, N.Y.) 2023:10.1007/s10126-023-10216-5. [PMID: 37246207 DOI: 10.1007/s10126-023-10216-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 05/12/2023] [Indexed: 05/30/2023]
Abstract
MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression via the recognition of their target messenger RNAs. MiR-10a-3p plays an important role in the process of ossification. In this study, we obtained the precursor sequence of miR-10a-3p in the pearl oyster Pinctada fucata martensii (Pm-miR-10a-3p) and verified its sequence by miR-RACE technology, and detected its expression level in the mantle tissues of the pearl oyster P. f. martensii. Pm-nAChRsα and Pm-NPY were identified as the potential target genes of Pm-miR-10a-3p. After the over-expression of Pm-miR-10a-3p, the target genes Pm-nAChRsα and Pm-NPY were downregulated, and the nacre microstructure became disordered. The Pm-miR-10a-3p mimic obviously inhibited the luciferase activity of the 3' untranslated region of the Pm-NPY gene. When the interaction site was mutated, the inhibitory effect disappeared. Our results suggested that Pm-miR-10a-3p participates in nacre formation in P. f. martensii by targeting Pm-NPY. This study can expand our understanding of the mechanism of biomineralization in pearl oysters.
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Affiliation(s)
- Min Yang
- Fishery College, Guangdong Ocean University, Zhanjiang, 524025, China
| | - Xin Lei Li
- Fishery College, Guangdong Ocean University, Zhanjiang, 524025, China
| | - Yu Ting Zhang
- Fishery College, Guangdong Ocean University, Zhanjiang, 524025, China
| | - Yue Wen Deng
- Fishery College, Guangdong Ocean University, Zhanjiang, 524025, China
- Pearl Breeding and Processing Engineering Technology Research Centre of Guangdong Province, Zhanjiang, 524088, China
- Guangdong Science and Innovation Center for Pearl Culture, Zhanjiang, 524088, China
- Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy culture, Zhanjiang, 524088, China
| | - Yu Jiao
- Fishery College, Guangdong Ocean University, Zhanjiang, 524025, China.
- Pearl Breeding and Processing Engineering Technology Research Centre of Guangdong Province, Zhanjiang, 524088, China.
- Guangdong Science and Innovation Center for Pearl Culture, Zhanjiang, 524088, China.
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19
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Assefa F. The role of sensory and sympathetic nerves in craniofacial bone regeneration. Neuropeptides 2023; 99:102328. [PMID: 36827755 DOI: 10.1016/j.npep.2023.102328] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 02/14/2023] [Accepted: 02/15/2023] [Indexed: 02/21/2023]
Abstract
Multiple factors regulate the regeneration of craniofacial bone defects. The nervous system is recognized as one of the critical regulators of bone mass, thereby suggesting a role for neuronal pathways in bone regeneration. However, in the context of craniofacial bone regeneration, little is known about the interplay between the nervous system and craniofacial bone. Sensory and sympathetic nerves interact with the bone through their neuropeptides, neurotransmitters, proteins, peptides, and amino acid derivates. The neuron-derived factors, such as semaphorin 3A (SEMA3A), substance P (SP), calcitonin gene-related peptide (CGRP), neuropeptide Y (NPY), and vasoactive intestinal peptide (VIP), possess a remarkable role in craniofacial regeneration. This review summarizes the roles of these factors and recently published factors such as secretoneurin (SN) and spexin (SPX) in the osteoblast and osteoclast differentiation, bone metabolism, growth, remodeling and discusses the novel application of nerve-based craniofacial bone regeneration. Moreover, the review will facilitate understanding the mechanism of action and provide potential treatment direction for the craniofacial bone defect.
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Affiliation(s)
- Freshet Assefa
- Department of Biochemistry, Collage of Medicine and Health Sciences, Hawassa University, P.O.Box 1560, Hawassa, Ethiopia.
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20
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Shin MK, Kim H, Choi SH, Kim BJ, Kwon O. Sex-specific bi‑directional association between osteoporosis and depression from the national representative data of South Korea. Sci Rep 2022; 12:9500. [PMID: 35680922 PMCID: PMC9184731 DOI: 10.1038/s41598-022-13401-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 05/24/2022] [Indexed: 11/16/2022] Open
Abstract
Both osteoporosis and depression are major health threats, but their interrelationship is not clear. This study elucidated the associations between osteoporosis and depression while considering the temporal sequence of the diagnoses. In this cross-sectional study, data were extracted from the Korean National Health and Nutrition Examination Surveys (2007-2009 and 2015-2019, n = 29,045). Osteoporosis and depression were defined by diagnoses thereof. The odds ratio (OR) of the incident osteoporosis among depression patients without a history of osteoporosis was calculated by multivariable logistic regression adjusted for potential confounders. A reverse association was also assessed. Participants were additionally stratified by their sex and age. As a result, male depression patients aged under 50 years showed higher ORs for osteoporosis than those without depression (OR 9.16, 95% CI 1.78-47.18). Female osteoporosis patients showed lower ORs for depression than those without osteoporosis (OR 0.71, 95% CI 0.58-0.88), especially in women aged 50 years and older. In the sensitivity analysis, the same results were obtained in women by their menopause status. Depression has a strong positive association with the occurrence of osteoporosis in young male adults, and osteoporosis has a negative association with the occurrence of depression in female adults.
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Affiliation(s)
- Min Kyoung Shin
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Korea
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, 03080, Korea
| | - Hyejin Kim
- Department of Public Health, Yonsei University Graduate School, Seoul, 03722, Korea
| | - Soo-Hee Choi
- Department of Psychiatry, Seoul National University College of Medicine, Seoul, 03080, Korea
- Department of Psychiatry, Seoul National University Hospital, Seoul, 03080, Korea
| | - Beom-Jun Kim
- Department of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea
| | - Obin Kwon
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Korea.
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, 03080, Korea.
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21
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Anderson ZT, Dawson AD, Slominski AT, Harris ML. Current Insights Into the Role of Neuropeptide Y in Skin Physiology and Pathology. Front Endocrinol (Lausanne) 2022; 13:838434. [PMID: 35418942 PMCID: PMC8996770 DOI: 10.3389/fendo.2022.838434] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/21/2022] [Indexed: 11/13/2022] Open
Abstract
Neuropeptide Y is widely distributed within the body and has long been implicated as a contributor to skin disease based on the correlative clinical data. However, until recently, there have been few empirical investigations to determine whether NPY has a pathophysiological role in the skin. Due to appearance-altering phenotypes of atopic dermatitis, psoriasis, and vitiligo, those suffering from these diseases often face multiple forms of negative social attention. This often results in psychological stress, which has been shown to exacerbate inflammatory skin diseases - creating a vicious cycle that perpetuates disease. This has been shown to drive severe depression, which has resulted in suicidal ideation being a comorbidity of these diseases. Herein, we review what is currently known about the associations of NPY with skin diseases and stress. We also review and provide educated guessing what the effects NPY can have in the skin. Inflammatory skin diseases can affect physical appearance to have significant, negative impacts on quality of life. No cure exists for these conditions, highlighting the need for identification of novel proteins/neuropetides, like NPY, that can be targeted therapeutically. This review sets the stage for future investigations into the role of NPY in skin biology and pathology to stimulate research on therapeutic targeting NPY signaling in order to combat inflammatory skin diseases.
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Affiliation(s)
- Zoya T. Anderson
- Department of Biology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Alex D. Dawson
- Department of Biology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Andrzej T. Slominski
- Department of Dermatology, Comprehensive Cancer Center, Cancer Chemoprevention Program, University of Alabama at Birmingham, Birmingham, AL, United States
- Veteran Administration Medical Center, Birmingham, AL, United States
| | - Melissa L. Harris
- Department of Biology, University of Alabama at Birmingham, Birmingham, AL, United States
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22
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Chen QC, Zhang Y. The Role of NPY in the Regulation of Bone Metabolism. Front Endocrinol (Lausanne) 2022; 13:833485. [PMID: 35273572 PMCID: PMC8902412 DOI: 10.3389/fendo.2022.833485] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Accepted: 01/20/2022] [Indexed: 11/13/2022] Open
Abstract
Bone diseases are the leading causes of disability and severely compromised quality of life. Neuropeptide Y (NPY) is a multifunctional neuropeptide that participates in various physiological and pathological processes and exists in both the nerve system and bone tissue. In bone tissue, it actively participates in bone metabolism and disease progression through its receptors. Previous studies have focused on the opposite effects of NPY on bone formation and resorption through paracrine modes. In this review, we present a brief overview of the progress made in this research field in recent times in order to provide reference for further understanding the regulatory mechanism of bone physiology and pathological metabolism.
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Affiliation(s)
- Qing-Chang Chen
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Yan Zhang
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Yan Zhang,
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23
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Kara Z, Güneş M, Bolayırlı İM, Oşar Siva Z. The Effects of Diabetic Polyneuropathy and Autonomic Neuropathy on Bone Turnover. Metab Syndr Relat Disord 2021; 20:11-19. [PMID: 34818066 DOI: 10.1089/met.2021.0028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background: The effect of diabetic polyneuropathy (DPN) and autonomic neuropathy (AN) on bone turnover in type 2 diabetes mellitus (DM) is uncertain due to the lack of data. In this study, we tried to determine the effect of DPN and AN on bone metabolism. Materials and Methods: The study included patients with type 2 DM (aged 18-80 years) and age-matched healthy individuals who presented to the Departments of Metabolism and Diabetes, Geriatrics, and General Internal Medicine, Cerrahpaşa Medical School, Istanbul University. The patients were examined to find out whether they had AN, and neuropathy scores were recorded by exploring peripheral neuropathy. Bone mineral density was measured by dual-energy X-ray (DXA). Demographic characteristics, the presence of microvascular complications, and biochemical data were obtained from patients' files. Serum cross-linked C-telopeptide (Ctx), osteocalcin, and bone-specific alkaline phosphatase (B-ALP) were analyzed. Results: The study comprised a total of 64 patients: 23 had type 2 DM and osteoporosis (OP) (duration of diabetes 10.1 ± 7 years; mean age 63 ± 9.1 years; female/male 18/5; Group 1), 41 had type 2 DM and non-OP (duration of diabetes 10.3 ± 7.6 years; mean age 58 ± 7.4 years; female/male 30/11; Group 2), and 26 healthy volunteers made up the control group (mean age 62 ± 11.9 years; female/male 14/12; Group 3). The bone turnover parameters were lower in type 2 DM individuals. The levels of osteocalcin (13.3 ± 5.2 ng/mL) and B-ALP (44.7 ± 10.9 IU/L) in patients with type 2 DM were lower than those of healthy subjects: osteocalcin (20.6 ± 10 ng/mL) and B-ALP (111 ± 31.4 IU/L; P = 0.001 and P = 0.000, respectively). Ctx levels (193.5 ± 49.3; 207.6 ± 40 ng/mL) were recorded to be similar (P = 0.2). AN was also noted as a risk factor for OP. For patients without AN, the likelihood of developing OP (odds ratio) was 0.7. The corresponding ratio for patients with AN was 9.3. Conclusions: Among the independent variables, the neuropathy score was determined to have an impact on bone turnover. AN was identified to be a significant risk factor for OP.
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Affiliation(s)
- Zehra Kara
- Department of Endocrinology, Metabolism and Diabetes, Cerrahpasa Medical Faculty, University of Istanbul-Cerrahpasa, Istanbul, Turkey
| | - Mutlu Güneş
- Division of Endocrinology, Metabolism and Diabetes, Bursa City Hospital, Bursa, Turkey
| | - İbrahim Murat Bolayırlı
- Department of Biochemistry, Cerrahpaşa Medical School, Istanbul University, Istanbul, Turkey
| | - Zeynep Oşar Siva
- Department of Endocrinology, Metabolism and Diabetes, Cerrahpasa Medical Faculty, University of Istanbul-Cerrahpasa, Istanbul, Turkey
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24
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Chen Y, Zhang T, Wan L, Wang Z, Li S, Hu J, Xu D, Lu H. Early treadmill running delays rotator cuff healing via Neuropeptide Y mediated inactivation of the Wnt/β-catenin signaling. J Orthop Translat 2021; 30:103-111. [PMID: 34722153 PMCID: PMC8517718 DOI: 10.1016/j.jot.2021.08.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 08/19/2021] [Accepted: 08/22/2021] [Indexed: 11/29/2022] Open
Abstract
Background Defining the optimal rehabilitation programs for rotator cuff healing remains a challenge. Early treadmill running may have negative effects on tendon-bone interface (TBI) healing with increased expression of Neuropeptide Y (NPY). However, the underlying mechanism is still unknown. Methods The mice were randomly assigned to four groups: control group, treadmill group, treadmill + BIBO3304 group and BIBO3304 group alone. Specifically, the control group was allowed free cage activity without any treatment after surgery. The treadmill group received early treadmill running initiated from postoperative day 2. The treadmill + BIBO3304 group received treadmill running combined with intra-articular injection of BIBO3304 postoperatively. The BIBO3304 group only received type 1 NPY receptor (Y1 receptor, Y1R) antagonist BIBO3304 postoperatively. Healing outcomes of the rotator cuff were evaluated by histological analysis, synchrotron radiation micro-computed tomography (SR-μCT) scanning, and biomechanical testing at 4 and 8 weeks after surgery. The expression of NPY and its Y1 receptor during the treadmill running were tested by immunofluorescence. In addition, the related signaling pathway of Neuropeptide Y among all groups was detected by immunohistochemistry and western-blot. Results Immunofluorescence results show that early treadmill training could lead to a significant increase in the expression of NPY at the healing site, and Y1R was widely expressed in both normal or injured rotator cuff without statistical difference. At the same time, early treadmill running delayed the healing of rotator cuff, as indicated with unsatisfactory outcomes, including a significantly lower histological score, decreased bone formation and inferior biomechanical properties at postoperative week 4 and 8. Moreover, the use of BIBO3304 could partly alleviate the negative effects of early treadmill running on the healing of rotator cuff and promote the natural healing process of rotator cuff, as evidenced by significant differences observed between the treadmill and treadmill + BIBO3304 groups, as well as observed between the control and BIBO3304 groups. On the other hand, the expressions of Wnt3a and β-catenin in the treadmill group were significantly lower compared with the other groups, while the expression in the BIBO3304 group was the highest, as evaluated by immunohistochemistry and western-blot. Conclusions Early treadmill running increased the expression of NPY at the RC healing site, which might burden the expression of Wnt3a/β-catenin and delay the healing process, inhibition of Y1 receptor with BIBO3304 could promote bone-tendon healing through the Wnt/β-catenin signaling. The translational potential of this article: This is the first study to evaluate the specific role of the NPY-Y1R axis and its underlying mechanism by which early treadmill running delays bone-tendon healing. Further, our study may provide references of precise and individualized exercise-based rehabilitation strategies for TBI healing in clinic. The translational potential of this article This is the first study to evaluate the specific role of the NPY-Y1R axis and its underlying mechanism by which early treadmill running delays bone-tendon healing. Further, our study may provide references of precise and individualized exercise-based rehabilitation strategies for TBI healing in clinic.
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Affiliation(s)
- Yang Chen
- Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China.,Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China
| | - Tao Zhang
- Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China.,Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China
| | - Liyang Wan
- Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China.,Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China
| | - Zhanwen Wang
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China
| | - Shengcan Li
- Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China.,Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China
| | - Jianzhong Hu
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China.,Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Daqi Xu
- Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China.,Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China
| | - Hongbin Lu
- Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China.,Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China
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25
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Abstract
Chronic stress has adverse consequences on many organ systems and physiological processes. However, existing protocols show large variability in response and are not suitable for female mice. Here, we provide a step-by-step protocol for establishing a reliable chronic stress model in mice that can be used in a variety of physiological settings. This protocol has been tested to be effective to produce a consistent response to stress in several mouse strains (C57BL/6J, 129X1/SvJ, B6.V-Lepob/J) and both sexes. For complete details on the use and execution of this protocol, please refer to Ip et al. (2019).
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Affiliation(s)
- Chi Kin Ip
- Neuroscience Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia
- St. Vincent’s Clinical School, UNSW Sydney, Sydney, NSW 2052, Australia
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26
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Wan Q, Qin W, Ma Y, Shen M, Li J, Zhang Z, Chen J, Tay FR, Niu L, Jiao K. Crosstalk between Bone and Nerves within Bone. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:2003390. [PMID: 33854888 PMCID: PMC8025013 DOI: 10.1002/advs.202003390] [Citation(s) in RCA: 113] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 10/29/2020] [Indexed: 05/11/2023]
Abstract
For the past two decades, the function of intrabony nerves on bone has been a subject of intense research, while the function of bone on intrabony nerves is still hidden in the corner. In the present review, the possible crosstalk between bone and intrabony peripheral nerves will be comprehensively analyzed. Peripheral nerves participate in bone development and repair via a host of signals generated through the secretion of neurotransmitters, neuropeptides, axon guidance factors and neurotrophins, with additional contribution from nerve-resident cells. In return, bone contributes to this microenvironmental rendezvous by housing the nerves within its internal milieu to provide mechanical support and a protective shelf. A large ensemble of chemical, mechanical, and electrical cues works in harmony with bone marrow stromal cells in the regulation of intrabony nerves. The crosstalk between bone and nerves is not limited to the physiological state, but also involved in various bone diseases including osteoporosis, osteoarthritis, heterotopic ossification, psychological stress-related bone abnormalities, and bone related tumors. This crosstalk may be harnessed in the design of tissue engineering scaffolds for repair of bone defects or be targeted for treatment of diseases related to bone and peripheral nerves.
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Affiliation(s)
- Qian‐Qian Wan
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of StomatologyDepartment of ProsthodonticsSchool of StomatologyThe Fourth Military Medical UniversityXi'anShaanxi710032China
| | - Wen‐Pin Qin
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of StomatologyDepartment of ProsthodonticsSchool of StomatologyThe Fourth Military Medical UniversityXi'anShaanxi710032China
| | - Yu‐Xuan Ma
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of StomatologyDepartment of ProsthodonticsSchool of StomatologyThe Fourth Military Medical UniversityXi'anShaanxi710032China
| | - Min‐Juan Shen
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of StomatologyDepartment of ProsthodonticsSchool of StomatologyThe Fourth Military Medical UniversityXi'anShaanxi710032China
| | - Jing Li
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of StomatologyDepartment of ProsthodonticsSchool of StomatologyThe Fourth Military Medical UniversityXi'anShaanxi710032China
| | - Zi‐Bin Zhang
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of StomatologyDepartment of ProsthodonticsSchool of StomatologyThe Fourth Military Medical UniversityXi'anShaanxi710032China
| | - Ji‐Hua Chen
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of StomatologyDepartment of ProsthodonticsSchool of StomatologyThe Fourth Military Medical UniversityXi'anShaanxi710032China
| | - Franklin R. Tay
- College of Graduate StudiesAugusta UniversityAugustaGA30912USA
| | - Li‐Na Niu
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of StomatologyDepartment of ProsthodonticsSchool of StomatologyThe Fourth Military Medical UniversityXi'anShaanxi710032China
| | - Kai Jiao
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of StomatologyDepartment of ProsthodonticsSchool of StomatologyThe Fourth Military Medical UniversityXi'anShaanxi710032China
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27
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Aveleira CA, Ferreira-Marques M, Cortes L, Valero J, Pereira D, Pereira de Almeida L, Cavadas C. Neuropeptide Y Enhances Progerin Clearance and Ameliorates the Senescent Phenotype of Human Hutchinson-Gilford Progeria Syndrome Cells. J Gerontol A Biol Sci Med Sci 2021; 75:1073-1078. [PMID: 32012215 PMCID: PMC7243588 DOI: 10.1093/gerona/glz280] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Indexed: 12/24/2022] Open
Abstract
Hutchinson-Gilford progeria syndrome (HGPS, or classical progeria) is a rare genetic disorder, characterized by premature aging, and caused by a de novo point mutation (C608G) within the lamin A/C gene (LMNA), producing an abnormal lamin A protein, termed progerin. Accumulation of progerin causes nuclear abnormalities and cell cycle arrest ultimately leading to cellular senescence. Autophagy impairment is a hallmark of cellular aging, and the rescue of this proteostasis mechanism delays aging progression in HGPS cells. We have previously shown that the endogenous Neuropeptide Y (NPY) increases autophagy in hypothalamus, a brain area already identified as a central regulator of whole-body aging. We also showed that NPY mediates caloric restriction-induced autophagy. These results are in accordance with other studies suggesting that NPY may act as a caloric restriction mimetic and plays a role as a lifespan and aging regulator. The aim of the present study was, therefore, to investigate if NPY could delay HGPS premature aging phenotype. Herein, we report that NPY increases autophagic flux and progerin clearance in primary cultures of human dermal fibroblasts from HGPS patients. NPY also rescues nuclear morphology and decreases the number of dysmorphic nuclei, a hallmark of HGPS cells. In addition, NPY decreases other hallmarks of aging as DNA damage and cellular senescence. Altogether, these results show that NPY rescues several hallmarks of cellular aging in HGPS cells, suggesting that NPY can be considered a promising strategy to delay or block the premature aging of HGPS.
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Affiliation(s)
- Célia A Aveleira
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
| | - Marisa Ferreira-Marques
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.,Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Luísa Cortes
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Jorge Valero
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
| | - Dina Pereira
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal.,Institute for Interdisciplinary Research , University of Coimbra, Coimbra, Portugal
| | - Luís Pereira de Almeida
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.,Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Cláudia Cavadas
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.,Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
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28
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Culibrk RA, Arabiyat AS, DeKalb CA, Hahn MS. Modeling Sympathetic Hyperactivity in Alzheimer's Related Bone Loss. J Alzheimers Dis 2021; 84:647-658. [PMID: 34569964 DOI: 10.3233/jad-215007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND A significant subset of patients with Alzheimer's disease (AD) exhibit low bone mineral density and are therefore more fracture-prone, relative to their similarly aged neurotypical counterparts. In addition to chronic immune hyperactivity, behavioral dysregulation of effector peripheral sympathetic neurons-which densely innervate bone and potently modulate bone remodeling-is implicated in this pathological bone reformation. OBJECTIVE Thus, there exists a pressing need for a robust in vitro model which allows interrogation of the paracrine interactions between the putative mediators of AD-related osteopenia: sympathetic neurons (SNs) and mesenchymal stem cells (MSCs). METHODS Toward this end, activated SN-like PC12 cells and bone marrow derived MSCs were cultured in poly(ethylene glycol) diacrylate (PEGDA) hydrogels in the presence or absence of the AD-relevant inflammatory cytokine tumor necrosis factor alpha (TNF-α) under mono- and co-culture conditions. RESULTS PC12s and MSCs exposed separately to TNF-α displayed increased expression of pro-inflammatory mediators and decreased osteopontin (OPN), respectively. These data indicate that TNF-α was capable of inducing a dysregulated state in both cell types consistent with AD. Co-culture of TNF-α-activated PC12s and MSCs further exacerbated pathological behaviors in both cell types. Specifically, PC12s displayed increased secretion of interleukin 6 relative to TNF-α stimulated monoculture controls. Similarly, MSCs demonstrated a further reduction in osteogenic capacity relative to TNF-α stimulated monoculture controls, as illustrated by a significant decrease in OPN and collagen type I alpha I chain. CONCLUSION Taken together, these data may indicate that dysregulated sympathetic activity may contribute to AD-related bone loss.
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Affiliation(s)
- Robert A Culibrk
- Hahn Tissue Lab, Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, USA
| | - Ahmad S Arabiyat
- Hahn Tissue Lab, Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, USA
| | - Carisa A DeKalb
- Hahn Tissue Lab, Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, USA
| | - Mariah S Hahn
- Hahn Tissue Lab, Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, USA
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29
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Wee NKY, Nguyen AD, Enriquez RF, Zhang L, Herzog H, Baldock PA. Neuropeptide Y Regulation of Energy Partitioning and Bone Mass During Cold Exposure. Calcif Tissue Int 2020; 107:510-523. [PMID: 32804252 DOI: 10.1007/s00223-020-00745-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 08/04/2020] [Indexed: 10/23/2022]
Abstract
The maintenance of whole body energy homeostasis is critical to survival and mechanisms exist whereby an organism can adapt to its environment and the stresses placed upon it. Environmental temperature and thermogenesis are key components known to affect energy balance. However, little is known about how these processes are balanced against the overall energy balance. We show that even mild cold exposure has a significant effect on energy expenditure and UCP-1 levels which increase by 43% and 400%, respectively, when wild-type (WT) mice at thermoneutral (29 °C) were compared to mice at room temperature (22 °C) conditions. Interestingly, bone mass was lower in cold-stressed WT mice with significant reductions in femoral bone mineral content (- 19%) and bone volume (- 13%). Importantly, these cold-induced skeletal changes were absent in mice lacking NPY, one of the main controllers of energy homeostasis, highlighting the critical role of NPY in this process. However, energy expenditure was significantly greater in cold-exposed NPY null mice, indicating that suppression of non-thermogenic tissues, like bone, contributes to the adaptive responses to cold exposure. Altogether, this work identifies NPY as being crucial in coordinating energy and bone homeostasis where it suppresses energy expenditure, UCP-1 levels and lowers bone mass under conditions of cold exposure.
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Affiliation(s)
- Natalie K Y Wee
- Bone Biology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW, 2010, Australia
| | - Amy D Nguyen
- Neuroscience Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW, 2010, Australia
| | - Ronaldo F Enriquez
- Bone Biology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW, 2010, Australia
| | - Lei Zhang
- Neuroscience Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW, 2010, Australia
| | - Herbert Herzog
- Neuroscience Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW, 2010, Australia
- School of Medical Sciences, University of NSW, Sydney, NSW, Australia
| | - Paul A Baldock
- Bone Biology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW, 2010, Australia.
- School of Medical Sciences, University of NSW, Sydney, NSW, Australia.
- School of Medicine Sydney, University of Notre Dame Australia, Sydney, Australia.
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30
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Wu JQ, Jiang N, Yu B. Mechanisms of action of neuropeptide Y on stem cells and its potential applications in orthopaedic disorders. World J Stem Cells 2020; 12:986-1000. [PMID: 33033559 PMCID: PMC7524693 DOI: 10.4252/wjsc.v12.i9.986] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 05/25/2020] [Accepted: 06/02/2020] [Indexed: 02/06/2023] Open
Abstract
Musculoskeletal disorders are the leading causes of disability and result in reduced quality of life. The neuro-osteogenic network is one of the most promising fields in orthopaedic research. Neuropeptide Y (NPY) system has been reported to be involved in the regulations of bone metabolism and homeostasis, which also provide feedback to the central NPY system via NPY receptors. Currently, potential roles of peripheral NPY in bone metabolism remain unclear. Growing evidence suggests that NPY can regulate biological actions of bone marrow mesenchymal stem cells, hematopoietic stem cells, endothelial cells, and chondrocytes via a local autocrine or paracrine manner by different NPY receptors. The regulative activities of NPY may be achieved through the plasticity of NPY receptors, and interactions among the targeted cells as well. In general, NPY can influence proliferation, apoptosis, differentiation, migration, mobilization, and cytokine secretion of different types of cells, and play crucial roles in the development of bone delayed/non-union, osteoporosis, and osteoarthritis. Further basic research should clarify detailed mechanisms of action of NPY on stem cells, and clinical investigations are also necessary to comprehensively evaluate potential applications of NPY and its receptor-targeted drugs in management of musculoskeletal disorders.
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Affiliation(s)
- Jian-Qun Wu
- Department of Orthopedics and Traumatology, Huadu District People’s Hospital, Guangzhou 510800, Guangdong Province, China
| | - Nan Jiang
- Division of Orthopaedics and Traumatology, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Bin Yu
- Division of Orthopaedics and Traumatology, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
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31
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Zhang B, Zhang X, Xiao J, Zhou X, Chen Y, Gao C. Neuropeptide Y upregulates Runx2 and osterix and enhances osteogenesis in mouse MC3T3‑E1 cells via an autocrine mechanism. Mol Med Rep 2020; 22:4376-4382. [PMID: 33000198 PMCID: PMC7533442 DOI: 10.3892/mmr.2020.11506] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 08/20/2020] [Indexed: 12/23/2022] Open
Abstract
The neuropeptide Y (NPY) system is considered one of the primary neural signaling pathways. NPY, produced by osteoblasts and other peripheral tissues, is known to inhibit biological functions of osteoblasts. However, until recently, little was known of the autocrine mechanism by which NPY is regulated. To investigate this mechanism, overexpression plasmids and small interfering RNA (siRNA) targeting NPY were transfected into the MC3T3-E1 cell line to observe its effects on osteogenesis. NPY overexpression was found to markedly enhance the osteogenic ability of MC3T3-E1 cells by an autocrine mechanism, coincident with the upregulation of osterix and runt-related transcription factor 2 (Runx2). Furthermore, NPY increased the activities of alkaline phosphatase (ALP) and osteocalcin (OCN) by upregulating their osteoblastic expression in vitro (as well as that of osterix and Runx2). Following transfection with NPY-siRNA, the osteoblastic ability of MC3T3-E1 cells was markedly decreased, and NPY deficiency inhibited the protein expression of osterix, Runx2, OCN and ALP in primary osteoblasts. Collectively, these results indicated that NPY played an important role in osteoblast differentiation by regulating the osterix and Runx2 pathways.
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Affiliation(s)
- Bo Zhang
- Department of Joint Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, P.R. China
| | - Xiaolei Zhang
- Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Juan Xiao
- Department of Evidence‑Based Medicine, Institute of Medical Sciences, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, P.R. China
| | - Xuguang Zhou
- Department of Joint Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, P.R. China
| | - Yuan Chen
- Departments of Central Research Lab, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, P.R. China
| | - Chunzheng Gao
- Departments of Spinal Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, P.R. China
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32
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Effects of Early Life Stress on Bone Homeostasis in Mice and Humans. Int J Mol Sci 2020; 21:ijms21186634. [PMID: 32927845 PMCID: PMC7556040 DOI: 10.3390/ijms21186634] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 08/27/2020] [Accepted: 09/05/2020] [Indexed: 11/16/2022] Open
Abstract
Bone pathology is frequent in stressed individuals. A comprehensive examination of mechanisms linking life stress, depression and disturbed bone homeostasis is missing. In this translational study, mice exposed to early life stress (MSUS) were examined for bone microarchitecture (μCT), metabolism (qPCR/ELISA), and neuronal stress mediator expression (qPCR) and compared with a sample of depressive patients with or without early life stress by analyzing bone mineral density (BMD) (DXA) and metabolic changes in serum (osteocalcin, PINP, CTX-I). MSUS mice showed a significant decrease in NGF, NPYR1, VIPR1 and TACR1 expression, higher innervation density in bone, and increased serum levels of CTX-I, suggesting a milieu in favor of catabolic bone turnover. MSUS mice had a significantly lower body weight compared to control mice, and this caused minor effects on bone microarchitecture. Depressive patients with experiences of childhood neglect also showed a catabolic pattern. A significant reduction in BMD was observed in depressive patients with childhood abuse and stressful life events during childhood. Therefore, future studies on prevention and treatment strategies for both mental and bone disease should consider early life stress as a risk factor for bone pathologies.
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33
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Yan FF, Wang WC, Cheng HW. Bacillus subtilis-based probiotic promotes bone growth by inhibition of inflammation in broilers subjected to cyclic heating episodes. Poult Sci 2020; 99:5252-5260. [PMID: 33142440 PMCID: PMC7647906 DOI: 10.1016/j.psj.2020.08.051] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 06/19/2020] [Accepted: 08/19/2020] [Indexed: 01/03/2023] Open
Abstract
Heat stress as an environmental stressor causes abnormal bone remodeling and microarchitectural deterioration. The objective of this study was to investigate the effects of a Bacillus subtilis–based probiotic on bone mass of broilers subjected to cycling high ambient temperature. One hundred and twenty 1-day-old Ross 708 male broiler chicks were randomly assigned to 2 dietary treatments (12 pens per treatment): control diet and the control diet plus 250-ppm probiotic consisting of 3 strains of Bacillus subtilis. Room temperature was gradually decreased from 35°C on day 1 by 0.5°C/d until day 15, when ambient temperature was increased from 28°C to 32°C for 10 h (07:00 h–17:00 h) daily until day 44. Samples of blood, leg bones (tibia and femur), and brains (raphe nuclei and hypothalamus) were collected at day 43, while latency to lie test was conducted at day 44. Compared with controls, probiotic supplementation increased bone mineral content, weight, size, weight to length index, and reduced robusticity index in the tibia and femur (P < 0.05) of broilers subjected to heat stress. Serum concentrations of c-terminal telopeptide of type I collagen (CTX) were reduced (P = 0.02) by the probiotic supplementation, while ionized calcium, phosphate, and osteocalcin were not affected (P > 0.05). Moreover, tumor necrosis factor-α (TNF-α) in probiotic fed broilers was decreased (P = 0.003) without changes of plasma interleukin (IL)-6, IL-10, interferon-γ, and corticosterone concentrations. There were no treatment effects on the concentrations of peripheral serotonin and central serotonin and catecholamines (norepinephrine, epinephrine, and dopamine) as well as their metabolites. These results may indicate that dietary supplementation of Bacillus subtilis–based probiotic increases bone growth in broilers under a cyclic heating episode probably via inhibition of bone resorption, resulting from downregulation of the circulating TNF-α and CTX. Dietary probiotic supplementation may be a management strategy for increasing skeletal health of broilers under hot weather.
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Affiliation(s)
- Fei-Fei Yan
- College of Animal Science and Technology College of Veterinary Medicine, Zhejiang A&F University, Hangzhou, Zhejiang 311300, China.
| | - Wei-Chao Wang
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA
| | - Heng-Wei Cheng
- USDA-ARS, Livestock Behavior Research Unit, West Lafayette, IN 47907, USA.
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Crosstalk of Brain and Bone-Clinical Observations and Their Molecular Bases. Int J Mol Sci 2020; 21:ijms21144946. [PMID: 32668736 PMCID: PMC7404044 DOI: 10.3390/ijms21144946] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 07/06/2020] [Accepted: 07/06/2020] [Indexed: 02/06/2023] Open
Abstract
As brain and bone disorders represent major health issues worldwide, substantial clinical investigations demonstrated a bidirectional crosstalk on several levels, mechanistically linking both apparently unrelated organs. While multiple stress, mood and neurodegenerative brain disorders are associated with osteoporosis, rare genetic skeletal diseases display impaired brain development and function. Along with brain and bone pathologies, particularly trauma events highlight the strong interaction of both organs. This review summarizes clinical and experimental observations reported for the crosstalk of brain and bone, followed by a detailed overview of their molecular bases. While brain-derived molecules affecting bone include central regulators, transmitters of the sympathetic, parasympathetic and sensory nervous system, bone-derived mediators altering brain function are released from bone cells and the bone marrow. Although the main pathways of the brain-bone crosstalk remain ‘efferent’, signaling from brain to bone, this review emphasizes the emergence of bone as a crucial ‘afferent’ regulator of cerebral development, function and pathophysiology. Therefore, unraveling the physiological and pathological bases of brain-bone interactions revealed promising pharmacologic targets and novel treatment strategies promoting concurrent brain and bone recovery.
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Winter EM, Ireland A, Butterfield NC, Haffner-Luntzer M, Horcajada MN, Veldhuis-Vlug AG, Oei L, Colaianni G, Bonnet N. Pregnancy and lactation, a challenge for the skeleton. Endocr Connect 2020; 9:R143-R157. [PMID: 32438342 PMCID: PMC7354730 DOI: 10.1530/ec-20-0055] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 05/12/2020] [Indexed: 12/19/2022]
Abstract
In this review we discuss skeletal adaptations to the demanding situation of pregnancy and lactation. Calcium demands are increased during pregnancy and lactation, and this is effectuated by a complex series of hormonal changes. The changes in bone structure at the tissue and whole bone level observed during pregnancy and lactation appear to largely recover over time. The magnitude of the changes observed during lactation may relate to the volume and duration of breastfeeding and return to regular menses. Studies examining long-term consequences of pregnancy and lactation suggest that there are small, site-specific benefits to bone density and that bone geometry may also be affected. Pregnancy- and lactation-induced osteoporosis (PLO) is a rare disease for which the pathophysiological mechanism is as yet incompletely known; here, we discuss and speculate on the possible roles of genetics, oxytocin, sympathetic tone and bone marrow fat. Finally, we discuss fracture healing during pregnancy and lactation and the effects of estrogen on this process.
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Affiliation(s)
- E M Winter
- Leiden University Medical Center, Department of Internal Medicine, Division of Endocrinology, Center for Bone Quality, Leiden, the Netherlands
- Correspondence should be addressed to E M Winter:
| | - A Ireland
- Musculoskeletal Science and Sports Medicine Research Centre, Department of Life Sciences, Manchester Metropolitan University, Manchester, United Kingdom
| | - N C Butterfield
- Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Imperial College London, Commonwealth Building, DuCane Road, London, United Kingdom
| | - M Haffner-Luntzer
- Institute of Orthopaedic Research and Biomechanics, University Medical Center Ulm, Ulm, Germany
| | - M-N Horcajada
- Nestlé Research, Department of Musculoskeletal Health, Innovation EPFL Park, Lausanne, Switzerland.
| | - A G Veldhuis-Vlug
- Leiden University Medical Center, Department of Internal Medicine, Division of Endocrinology, Center for Bone Quality, Leiden, the Netherlands
- Jan van Goyen Medical Center, Department of Internal Medicine, Amsterdam, the Netherlands
| | - L Oei
- Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
- Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - G Colaianni
- Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - N Bonnet
- Nestlé Research, Department of Musculoskeletal Health, Innovation EPFL Park, Lausanne, Switzerland.
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Tomlinson RE, Christiansen BA, Giannone AA, Genetos DC. The Role of Nerves in Skeletal Development, Adaptation, and Aging. Front Endocrinol (Lausanne) 2020; 11:646. [PMID: 33071963 PMCID: PMC7538664 DOI: 10.3389/fendo.2020.00646] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 08/07/2020] [Indexed: 12/24/2022] Open
Abstract
The skeleton is well-innervated, but only recently have the functions of this complex network in bone started to become known. Although our knowledge of skeletal sensory and sympathetic innervation is incomplete, including the specific locations and subtypes of nerves in bone, we are now able to reconcile early studies utilizing denervation models with recent work dissecting the molecular signaling between bone and nerve. In total, sensory innervation functions in bone much as it does elsewhere in the body-to sense and respond to stimuli, including mechanical loading. Similarly, sympathetic nerves regulate autonomic functions related to bone, including homeostatic remodeling and vascular tone. However, more study is required to translate our current knowledge of bone-nerve crosstalk to novel therapeutic strategies that can be effectively utilized to combat skeletal diseases, disorders of low bone mass, and age-related decreases in bone quality.
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Affiliation(s)
- Ryan E. Tomlinson
- Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, PA, United States
- *Correspondence: Ryan E. Tomlinson
| | - Blaine A. Christiansen
- Department of Orthopaedic Surgery, School of Medicine, University of California, Davis, Sacramento, CA, United States
| | - Adrienne A. Giannone
- Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States
| | - Damian C. Genetos
- Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States
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Mechanisms of Calorie Restriction: A Review of Genes Required for the Life-Extending and Tumor-Inhibiting Effects of Calorie Restriction. Nutrients 2019; 11:nu11123068. [PMID: 31888201 PMCID: PMC6950657 DOI: 10.3390/nu11123068] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 12/12/2019] [Accepted: 12/13/2019] [Indexed: 12/30/2022] Open
Abstract
This review focuses on mechanisms of calorie restriction (CR), particularly the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis as an evolutionary conserved signal that regulates aging and lifespan, underlying the effects of CR in mammals. Topics include (1) the relation of the GH-IGF-1 signal with chronic low-level inflammation as one of the possible causative factors of aging, that is, inflammaging, (2) the isoform specificity of the forkhead box protein O (FoxO) transcription factors in CR-mediated regulation of cancer and lifespan, (3) the role for FoxO1 in the tumor-inhibiting effect of CR, (4) pleiotropic roles for FoxO1 in the regulation of disorders, and (5) sirtuin (Sirt) as a molecule upstream of FoxO. From the evolutionary view, the necessity of neuropeptide Y (Npy) for the effects of CR and the pleiotropic roles for Npy in life stages are also emphasized. Genes for mediating the effects of CR and regulating aging are context-dependent, particularly depending on nutritional states.
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38
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Zenz G, Farzi A, Fröhlich EE, Reichmann F, Holzer P. Intranasal Neuropeptide Y Blunts Lipopolysaccharide-Evoked Sickness Behavior but Not the Immune Response in Mice. Neurotherapeutics 2019; 16:1335-1349. [PMID: 31338703 PMCID: PMC6985076 DOI: 10.1007/s13311-019-00758-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Neuropeptide Y (NPY) has been demonstrated to exert stress buffering effects and promote resilience. Non-invasive intranasal (IN) application of NPY to rodents is able to mitigate traumatic stress-induced behavioral changes as well as dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. However, it is unknown whether IN NPY could prevent the behavioral, pro-inflammatory and neurochemical responses to peripheral immune activation by the Toll-like receptor 4 (TLR4) stimulant lipopolysaccharide (LPS). Therefore, we analyzed the effects of IN NPY (100 μg) on the behavioral sickness response (reduced locomotion and exploration) and the underlying molecular mechanisms, 3 h and 21 h after intraperitoneal injections of LPS (0.03 mg/kg) in male C57BL/6N mice. The acute behavioral sickness response was significantly dampened by pretreatment with IN NPY 3 h after LPS injection. This effect was accompanied by diminished weight loss and lowered plasma corticosterone (CORT) levels 21 h after LPS injection. In contrast, acute circulating cytokine levels and hypothalamic cytokine mRNA expression remained unaltered by IN NPY, which indicates that the peripheral and cerebral immune response to LPS was left undisturbed. Our findings are in agreement with the reported activity of NPY to dampen the response of the HPA axis to stress. We propose that IN NPY ablates sickness behavior at a site beyond the peripheral and cerebral cytokine response, an action that is associated with reduced activity of the HPA axis as determined by decreased plasma CORT.These results indicate that IN NPY administration may be relevant to the management of neuropsychiatric disorders arising from immune-induced neuroendocrine dysfunction.
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Affiliation(s)
- Geraldine Zenz
- Research Unit of Translational Neurogastroenterology, Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Universitätsplatz 4, A-8010, Graz, Austria.
| | - Aitak Farzi
- Research Unit of Translational Neurogastroenterology, Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Universitätsplatz 4, A-8010, Graz, Austria
| | - Esther E Fröhlich
- Research Unit of Translational Neurogastroenterology, Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Universitätsplatz 4, A-8010, Graz, Austria
| | - Florian Reichmann
- Research Unit of Translational Neurogastroenterology, Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Universitätsplatz 4, A-8010, Graz, Austria
| | - Peter Holzer
- Research Unit of Translational Neurogastroenterology, Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Universitätsplatz 4, A-8010, Graz, Austria
- BioTechMed-Graz, Mozartgasse 12, A-8010, Graz, Austria
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39
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Ip CK, Zhang L, Farzi A, Qi Y, Clarke I, Reed F, Shi YC, Enriquez R, Dayas C, Graham B, Begg D, Brüning JC, Lee NJ, Hernandez-Sanchez D, Gopalasingam G, Koller J, Tasan R, Sperk G, Herzog H. Amygdala NPY Circuits Promote the Development of Accelerated Obesity under Chronic Stress Conditions. Cell Metab 2019; 30:111-128.e6. [PMID: 31031093 DOI: 10.1016/j.cmet.2019.04.001] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2018] [Revised: 02/16/2019] [Accepted: 04/02/2019] [Indexed: 12/22/2022]
Abstract
Neuropeptide Y (NPY) exerts a powerful orexigenic effect in the hypothalamus. However, extra-hypothalamic nuclei also produce NPY, but its influence on energy homeostasis is unclear. Here we uncover a previously unknown feeding stimulatory pathway that is activated under conditions of stress in combination with calorie-dense food; NPY neurons in the central amygdala are responsible for an exacerbated response to a combined stress and high-fat-diet intervention. Central amygdala NPY neuron-specific Npy overexpression mimics the obese phenotype seen in a combined stress and high-fat-diet model, which is prevented by the selective ablation of Npy. Using food intake and energy expenditure as readouts, we demonstrate that selective activation of central amygdala NPY neurons results in increased food intake and decreased energy expenditure. Mechanistically, it is the diminished insulin signaling capacity on central amygdala NPY neurons under combined stress and high-fat-diet conditions that leads to the exaggerated development of obesity.
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Affiliation(s)
- Chi Kin Ip
- Neuroscience Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia
| | - Lei Zhang
- Neuroscience Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia
| | - Aitak Farzi
- Neuroscience Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia
| | - Yue Qi
- Neuroscience Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia
| | - Ireni Clarke
- Neuroscience Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia
| | - Felicia Reed
- Neuroscience Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia
| | - Yan-Chuan Shi
- Neuroscience Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia
| | - Ronaldo Enriquez
- Neuroscience Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia
| | - Chris Dayas
- School of Biomedical Sciences & Pharmacy, University of Newcastle, Newcastle, NSW, Australia
| | - Bret Graham
- School of Biomedical Sciences & Pharmacy, University of Newcastle, Newcastle, NSW, Australia
| | - Denovan Begg
- School of Psychology, University of New South Wales, Sydney, NSW 2052, Australia
| | - Jens C Brüning
- Max Planck Institute for Metabolism Research, Cologne, Germany
| | - Nicola J Lee
- Neuroscience Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia
| | - Diana Hernandez-Sanchez
- Neuroscience Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia
| | - Gopana Gopalasingam
- Neuroscience Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia
| | - Julia Koller
- Neuroscience Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia
| | - Ramon Tasan
- Department of Pharmacology, Medical University Innsbruck, Innsbruck 6020, Austria
| | - Günther Sperk
- Department of Pharmacology, Medical University Innsbruck, Innsbruck 6020, Austria
| | - Herbert Herzog
- Neuroscience Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia.
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40
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Lee NJ, Clarke IM, Zengin A, Enriquez RF, Nagy V, Penninger JM, Baldock PA, Herzog H. RANK deletion in neuropeptide Y neurones attenuates oestrogen deficiency-related bone loss. J Neuroendocrinol 2019; 31:e12687. [PMID: 30633834 DOI: 10.1111/jne.12687] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 01/06/2019] [Accepted: 01/07/2019] [Indexed: 12/17/2022]
Abstract
The RANKL pathway is known to be an important aspect of the pathogenesis of oestrogen deficiency-induced bone loss. RANK deletion specifically in neuropeptide Y (NPY) neurones has been shown to enhance the ability of the skeleton to match increases in body weight caused by high-fat diet feeding, likely via the modulation of NPY levels. In the present study, we used ovariectomy in female mice to show that RANK deletion in NPY neurones attenuates bone loss caused by long-term oestrogen deficiency, particularly in the vertebral compartment. Ovariectomy led to a reduction in NPY expression levels in the arcuate nucleus of NPYcre/+ ;RANKlox/lox mice compared to NPYcre/+ ;RANKlox/+ controls. Because NPY deficient mice also displayed a similar protection against ovariectomy-induced bone loss, modulation of hypothalamic NPY signalling is the likely mechanism behind the protection from bone loss in the NPYcre/+ ;RANKlox/lox mice.
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Affiliation(s)
- Nicola J Lee
- Neuroscience Division, Garvan Institute, St Vincent's Hospital, Darlinghurst, New South Wales, Australia
- St Vincents Clinical School, UNSW Sydney, Sydney, New South Wales, Australia
| | - Ireni M Clarke
- Neuroscience Division, Garvan Institute, St Vincent's Hospital, Darlinghurst, New South Wales, Australia
| | - Ayse Zengin
- Bone Biology Division, Garvan Institute, St Vincent's Hospital, Darlinghurst, New South Wales, Australia
| | - Ronaldo F Enriquez
- Neuroscience Division, Garvan Institute, St Vincent's Hospital, Darlinghurst, New South Wales, Australia
- Bone Biology Division, Garvan Institute, St Vincent's Hospital, Darlinghurst, New South Wales, Australia
| | - Vanj Nagy
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Josef M Penninger
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria
| | - Paul A Baldock
- St Vincents Clinical School, UNSW Sydney, Sydney, New South Wales, Australia
- Bone Biology Division, Garvan Institute, St Vincent's Hospital, Darlinghurst, New South Wales, Australia
| | - Herbert Herzog
- Neuroscience Division, Garvan Institute, St Vincent's Hospital, Darlinghurst, New South Wales, Australia
- St Vincents Clinical School, UNSW Sydney, Sydney, New South Wales, Australia
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41
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Wee NKY, Sinder BP, Novak S, Wang X, Stoddard C, Matthews BG, Kalajzic I. Skeletal phenotype of the neuropeptide Y knockout mouse. Neuropeptides 2019; 73:78-88. [PMID: 30522780 PMCID: PMC6326877 DOI: 10.1016/j.npep.2018.11.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Revised: 11/04/2018] [Accepted: 11/28/2018] [Indexed: 10/27/2022]
Abstract
Neuropeptide Y (NPY) is involved in multiple processes such as behavior, energy and bone metabolism. Previous studies have relied on global NPY depletion to examine its effects on bone. However, this approach is unable to distinguish the central or local source of NPY influencing bone. Our aim was to identify which cells within the skeleton express Npy and establish a model that will enable us to differentiate effects of NPY derived from different cell types. We have generated the NPY floxed (NPYflox) mice using CRISPR technology. By crossing the NPYflox mice with Hypoxanthine Phosphoribosyltransferase 1 (Hprt)-cre to generate a global knockout, we were able to validate and confirm loss of Npy transcript and protein in our global NPYKO. Global deletion of NPY results in a smaller femoral cortical cross-sectional area (-12%) and reduced bone strength (-18%) in male mice. In vitro, NPY-deficient bone marrow stromal cells (BMSCs) showed increase in osteogenic differentiation detected by increases in alkaline phosphatase staining and bone sialoprotein and osteocalcin expression. Despite both sexes presenting with increased adiposity, female mice had no alterations in bone mass, suggesting that NPY may have sex-specific effects on bone. In this study we identified Npy expression in the skeleton and examined the effect of global NPY depletion to bone mass. The differential impact of NPY deletion in cortical and cancellous compartments along with differences in phenotypes between in vitro and in vivo, highlights the complex nature of NPY signaling, indicative of distinct sources that can be dissected in the future using this NPYflox model.
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Affiliation(s)
- Natalie K Y Wee
- Department of Reconstructive Sciences, Farmington, CT 06030, USA
| | | | - Sanja Novak
- Department of Reconstructive Sciences, Farmington, CT 06030, USA
| | - Xi Wang
- Department of Reconstructive Sciences, Farmington, CT 06030, USA
| | - Chris Stoddard
- Genetics and Genome Sciences, UConn Health, Farmington, CT 06030, USA
| | - Brya G Matthews
- Department of Reconstructive Sciences, Farmington, CT 06030, USA; Department of Molecular Medicine and Pathology, University of Auckland, Auckland 1023, New Zealand
| | - Ivo Kalajzic
- Department of Reconstructive Sciences, Farmington, CT 06030, USA.
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Abstract
It is from the discovery of leptin and the central nervous system as a regulator of bone remodeling that the presence of autonomic nerves within the skeleton transitioned from a mere histological observation to the mechanism whereby neurons of the central nervous system communicate with cells of the bone microenvironment and regulate bone homeostasis. This shift in paradigm sparked new preclinical and clinical investigations aimed at defining the contribution of sympathetic, parasympathetic, and sensory nerves to the process of bone development, bone mass accrual, bone remodeling, and cancer metastasis. The aim of this article is to review the data that led to the current understanding of the interactions between the autonomic and skeletal systems and to present a critical appraisal of the literature, bringing forth a schema that can put into physiological and clinical context the main genetic and pharmacological observations pointing to the existence of an autonomic control of skeletal homeostasis. The different types of nerves found in the skeleton, their functional interactions with bone cells, their impact on bone development, bone mass accrual and remodeling, and the possible clinical or pathophysiological relevance of these findings are discussed.
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Affiliation(s)
- Florent Elefteriou
- Department of Molecular and Human Genetics and Orthopedic Surgery, Center for Skeletal Medicine and Biology, Baylor College of Medicine , Houston, Texas
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Abstract
INTRODUCTION Depression and posttraumatic stress disorder (PTSD) are two complex and debilitating psychiatric disorders that result in poor life and destructive behaviors against self and others. Currently, diagnosis is based on subjective rather than objective determinations leading to misdiagnose and ineffective treatments. Advances in novel neurobiological methods have allowed assessment of promising biomarkers to diagnose depression and PTSD, which offers a new means of appropriately treating patients. Areas covered: Biomarkers discovery in blood represents a fundamental tool to predict, diagnose, and monitor treatment efficacy in depression and PTSD. The potential role of altered HPA axis, epigenetics, NPY, BDNF, neurosteroid biosynthesis, the endocannabinoid system, and their function as biomarkers for mood disorders is discussed. Insofar, we propose the identification of a biomarker axis to univocally identify and discriminate disorders with large comorbidity and symptoms overlap, so as to provide a base of support for development of targeted treatments. We also weigh in on the feasibility of a future blood test for early diagnosis. Expert commentary: Potential biomarkers have already been assessed in patients' blood and need to be further validated through multisite large clinical trial stratification. Another challenge is to assess the relation among several interdependent biomarkers to form an axis that identifies a specific disorder and secures the best-individualized treatment. The future of blood-based tests for PTSD and depression is not only on the horizon but, possibly, already around the corner.
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Affiliation(s)
- Dario Aspesi
- a The Psychiatric Institute, Department of Psychiatry , University of Illinois at Chicago , Chicago , IL , USA
| | - Graziano Pinna
- a The Psychiatric Institute, Department of Psychiatry , University of Illinois at Chicago , Chicago , IL , USA
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Lee NJ, Clarke IM, Enriquez RF, Nagy V, Penninger J, Baldock PA, Herzog H. Central RANK signalling in NPY neurons alters bone mass in male mice. Neuropeptides 2018; 68:75-83. [PMID: 29477253 DOI: 10.1016/j.npep.2018.02.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 02/05/2018] [Accepted: 02/14/2018] [Indexed: 11/23/2022]
Abstract
RANKL signalling known to be important for the control of bone mass, has recently also been implicated in the brain to control thermoregulation, however, it is not known which neuronal pathways are involved and whether other aspects of energy homeostasis are also affected. Here we show that selective deletion of RANK from NPY neurons down-regulated NPY mRNA expression in the hypothalamus. While comprehensive phenotyping of germline-induced NPY neuron specific RANK deficient mice revealed no significant changes in physical or metabolic parameters, adult onset deletion of RANK from NPY neurons led to a significant increase in fat mass and a decrease in whole body bone mineral content and bone mineral density. Intriguingly, when these conditional knockout mice were placed on a high fat diet, body weight and fat mass did not differ to control mice. However, they were able to significantly increase their bone mass to match their increased body weight, an ability that was lacking in control mice. Taken together, results from this study demonstrate that RANK signalling in NPY neurons is involved in modulating NPY levels and through that matching bone mass to body weight.
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Affiliation(s)
- N J Lee
- Neuroscience Division, Garvan Institute, St Vincent's Hospital, Darlinghurst, NSW, Australia; St Vincents Clinical School, UNSW Sydney, Sydney, NSW, Australia.
| | - I M Clarke
- Neuroscience Division, Garvan Institute, St Vincent's Hospital, Darlinghurst, NSW, Australia
| | - R F Enriquez
- Neuroscience Division, Garvan Institute, St Vincent's Hospital, Darlinghurst, NSW, Australia; St Vincents Clinical School, UNSW Sydney, Sydney, NSW, Australia
| | - V Nagy
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), 1030 Vienna, Austria
| | - J Penninger
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), 1030 Vienna, Austria
| | - P A Baldock
- Bone Biology Division, Garvan Institute, St Vincent's Hospital, Darlinghurst, NSW, Australia; St Vincents Clinical School, UNSW Sydney, Sydney, NSW, Australia
| | - H Herzog
- Neuroscience Division, Garvan Institute, St Vincent's Hospital, Darlinghurst, NSW, Australia; St Vincents Clinical School, UNSW Sydney, Sydney, NSW, Australia
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45
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Deis S, Srivastava RK, Ruiz de Azua I, Bindila L, Baraghithy S, Lutz B, Bab I, Tam J. Age-related regulation of bone formation by the sympathetic cannabinoid CB1 receptor. Bone 2018; 108:34-42. [PMID: 29274505 DOI: 10.1016/j.bone.2017.12.018] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 12/03/2017] [Accepted: 12/19/2017] [Indexed: 01/09/2023]
Abstract
The endocannabinoid (eCB) system, including its receptors, ligands, and their metabolizing enzymes, plays an important role in bone physiology. Skeletal cannabinoid type 1 (CB1) receptor signaling transmits retrograde signals that restrain norepinephrine (NE) release, thus transiently stimulating bone formation following an acute challenge, suggesting a feedback circuit between sympathetic nerve terminals and osteoblasts. To assess the effect of chronic in vivo occurrence of this circuit, we characterized the skeletal phenotype of mice with a conditional deletion of the CB1 receptor in adrenergic/noradrenergic cells, including sympathetic nerves. Whereas the deletion of the CB1 receptor did not affect bone mass accrual in the distal femoral metaphysis and in vertebral bodies of young, 12-week-old mice, it substantially increased bone mass in aged, 35-week-old mutant mice as compared to wild-type controls. Contrary to our expectations, specific deficiency of the CB1 receptor in sympathetic neurons led to a markedly increased bone mass phenotype, associated with an enhanced bone formation rate and reduced osteoclastogenesis. Mechanistically, the reduced skeletal eCB 'tone' in the null mice did not reflect in increased sympathetic tone and reduced bone formation, suggesting that constitutive genetic inactivation of sympathetic CB1 receptor disrupts the negative feedback loop between eCBs and NE signaling in bone.
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Affiliation(s)
- Saif Deis
- Bone Laboratory, Hebrew University of Jerusalem, Jerusalem, Israel; Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel
| | - Raj Kamal Srivastava
- Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Germany
| | - Inigo Ruiz de Azua
- Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Germany
| | - Laura Bindila
- Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Germany
| | - Saja Baraghithy
- Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel
| | - Beat Lutz
- Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Germany
| | - Itai Bab
- Bone Laboratory, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Joseph Tam
- Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel.
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Nguyen AD, Lee NJ, Wee NKY, Zhang L, Enriquez RF, Khor EC, Nie T, Wu D, Sainsbury A, Baldock PA, Herzog H. Uncoupling protein-1 is protective of bone mass under mild cold stress conditions. Bone 2018; 106:167-178. [PMID: 26055106 DOI: 10.1016/j.bone.2015.05.037] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Revised: 05/25/2015] [Accepted: 05/27/2015] [Indexed: 12/16/2022]
Abstract
Brown adipose tissue (BAT), largely controlled by the sympathetic nervous system (SNS), has the ability to dissipate energy in the form of heat through the actions of uncoupling protein-1 (UCP-1), thereby critically influencing energy expenditure. Besides BAT, the SNS also strongly influences bone, and recent studies have demonstrated a positive correlation between BAT activity and bone mass, albeit the interactions between BAT and bone remain unclear. Here we show that UCP-1 is critical for protecting bone mass in mice under conditions of permanent mild cold stress for this species (22°C). UCP-1-/- mice housed at 22°C showed significantly lower cancellous bone mass, with lower trabecular number and thickness, a lower bone formation rate and mineralising surface, but unaltered osteoclast number, compared to wild type mice housed at the same temperature. UCP-1-/- mice also displayed shorter femurs than wild types, with smaller cortical periosteal and endocortical perimeters. Importantly, these altered bone phenotypes were not observed when UCP-1-/- and wild type mice were housed in thermo-neutral conditions (29°C), indicating a UCP-1 dependent support of bone mass and bone formation at the lower temperature. Furthermore, at 22°C UCP-1-/- mice showed elevated hypothalamic expression of neuropeptide Y (NPY) relative to wild type, which is consistent with the lower bone formation and mass of UCP-1-/- mice at 22°C caused by the catabolic effects of hypothalamic NPY-induced SNS modulation. The results from this study suggest that during mild cold stress, when BAT-dependent thermogenesis is required, UCP-1 activity exerts a protective effect on bone mass possibly through alterations in central NPY pathways known to regulate SNS activity.
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Affiliation(s)
- Amy D Nguyen
- Neuroscience Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia
| | - Nicola J Lee
- Neuroscience Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia
| | - Natalie K Y Wee
- Osteoporosis and Bone Biology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia
| | - Lei Zhang
- Neuroscience Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia
| | - Ronaldo F Enriquez
- Osteoporosis and Bone Biology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia
| | - Ee Cheng Khor
- Osteoporosis and Bone Biology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia
| | - Tao Nie
- Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510663, China
| | - Donghai Wu
- Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510663, China
| | - Amanda Sainsbury
- Neuroscience Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia; The Boden Institute of Obesity, Nutrition, Exercise & Eating Disorders, Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia
| | - Paul A Baldock
- Osteoporosis and Bone Biology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia
| | - Herbert Herzog
- Neuroscience Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia; Faculty of Medicine, University of NSW, Kensington, Sydney, NSW 2052, Australia.
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Foertsch S, Haffner-Luntzer M, Kroner J, Gross F, Kaiser K, Erber M, Reber SO, Ignatius A. Chronic psychosocial stress disturbs long-bone growth in adolescent mice. Dis Model Mech 2017; 10:1399-1409. [PMID: 28982680 PMCID: PMC5769608 DOI: 10.1242/dmm.030916] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Accepted: 09/30/2017] [Indexed: 01/13/2023] Open
Abstract
Although a strong association between psychiatric and somatic disorders is generally accepted, little is known regarding the interrelationship between mental and skeletal health. Although depressive disorders have been shown to be strongly associated with osteoporosis and increased fracture risk, evidence from post-traumatic stress disorder (PTSD) patients is less consistent. Therefore, the present study investigated the influence of chronic psychosocial stress on bone using a well-established murine model for PTSD. C57BL/6N mice (7 weeks old) were subjected to chronic subordinate colony housing (CSC) for 19 days, whereas control mice were singly housed. Anxiety-related behavior was assessed in the open-field/novel-object test, after which the mice were euthanized to assess endocrine and bone parameters. CSC mice exhibited increased anxiety-related behavior in the open-field/novel-object test, increased adrenal and decreased thymus weights, and unaffected plasma morning corticosterone. Microcomputed tomography and histomorphometrical analyses revealed significantly reduced tibia and femur lengths, increased growth-plate thickness and reduced mineral deposition at the growth plate, suggesting disturbed endochondral ossification during long-bone growth. This was associated with reduced Runx2 expression in hypertrophic chondrocytes in the growth plate. Trabecular thicknesses and bone mineral density were significantly increased in CSC compared to singly housed mice. Tyrosine hydroxylase expression was increased in bone marrow cells located at the growth plates of CSC mice, implying that local adrenergic signaling might be involved in the effects of CSC on the skeletal phenotype. In conclusion, chronic psychosocial stress negatively impacts endochondral ossification in the growth plate, affecting both longitudinal and appositional bone growth in adolescent mice.
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Affiliation(s)
- Sandra Foertsch
- Laboratory for Molecular Psychosomatics, Clinic for Psychosomatic Medicine and Psychotherapy, University, 89081 Ulm, Germany
| | - Melanie Haffner-Luntzer
- Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, 89081 Ulm, Germany
| | - Jochen Kroner
- Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, 89081 Ulm, Germany
| | - Florian Gross
- Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, 89081 Ulm, Germany
| | - Kathrin Kaiser
- Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, 89081 Ulm, Germany
| | - Maike Erber
- Laboratory for Molecular Psychosomatics, Clinic for Psychosomatic Medicine and Psychotherapy, University, 89081 Ulm, Germany
| | - Stefan O Reber
- Laboratory for Molecular Psychosomatics, Clinic for Psychosomatic Medicine and Psychotherapy, University, 89081 Ulm, Germany
| | - Anita Ignatius
- Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, 89081 Ulm, Germany
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Henneicke H, Li J, Kim S, Gasparini SJ, Seibel MJ, Zhou H. Chronic Mild Stress Causes Bone Loss via an Osteoblast-Specific Glucocorticoid-Dependent Mechanism. Endocrinology 2017; 158:1939-1950. [PMID: 28368468 DOI: 10.1210/en.2016-1658] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Accepted: 02/16/2017] [Indexed: 12/26/2022]
Abstract
Chronic stress and depression are associated with alterations in the hypothalamic-pituitary-adrenal signaling cascade and considered a risk factor for bone loss and fractures. However, the mechanisms underlying the association between stress and poor bone health are unclear. Using a transgenic (tg) mouse model in which glucocorticoid signaling is selectively disrupted in mature osteoblasts and osteocytes [11β-hydroxysteroid-dehydrogenase type 2 (HSD2)OB-tg mice], the present study examines the impact of chronic stress on skeletal metabolism and structure. Eight-week-old male and female HSD2OB-tg mice and their wild-type (WT) littermates were exposed to chronic mild stress (CMS) for the duration of 4 weeks. At the endpoint, L3 vertebrae and tibiae were analyzed by micro-computed tomography and histomorphometry, and bone turnover was measured biochemically. Compared with nonstressed controls, exposure to CMS caused an approximately threefold increase in serum corticosterone concentrations in WT and HSD2OB-tg mice of both genders. Compared with controls, CMS resulted in loss of vertebral trabecular bone mass in male WT mice but not in male HSD2OB-tg littermates. Furthermore, both tibial cortical area and area fraction were reduced in stressed WT but not in stressed HSD2OB-tg male mice. Osteoclast activity and bone resorption marker were increased in WT males following CMS, features absent in HSD2OB-tg males. Interestingly, CMS had little effect on vertebral and long-bone structural parameters in female mice. We conclude that in male mice, bone loss during CMS is mediated via enhanced glucocorticoid signaling in osteoblasts (and osteocytes) and subsequent activation of osteoclasts. Female mice appear resistant to the skeletal effects of CMS.
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Affiliation(s)
- Holger Henneicke
- Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, New South Wales 2139, Australia
| | - Jingbao Li
- Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, New South Wales 2139, Australia
- Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environmental Biophysics, School of Life Sciences, Northwestern Polytechnical University, Shaanxi 710000, China
| | - Sarah Kim
- Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, New South Wales 2139, Australia
| | - Sylvia J Gasparini
- Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, New South Wales 2139, Australia
| | - Markus J Seibel
- Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, New South Wales 2139, Australia
- Department of Endocrinology and Metabolism, Concord Hospital, University of Sydney, Sydney, New South Wales 2139, Australia
| | - Hong Zhou
- Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, New South Wales 2139, Australia
- Department of Endocrinology and Metabolism, Concord Hospital, University of Sydney, Sydney, New South Wales 2139, Australia
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49
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Glorie L, D'Haese PC, Verhulst A. Boning up on DPP4, DPP4 substrates, and DPP4-adipokine interactions: Logical reasoning and known facts about bone related effects of DPP4 inhibitors. Bone 2016; 92:37-49. [PMID: 27535784 DOI: 10.1016/j.bone.2016.08.009] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Revised: 07/29/2016] [Accepted: 08/11/2016] [Indexed: 12/19/2022]
Abstract
Dipeptidyl peptidase 4 (DPP4) is a conserved exopeptidase with an important function in protein regulation. The activity of DPP4, an enzyme which can either be anchored to the plasma membrane or circulate free in the extracellular compartment, affects the glucose metabolism, cellular signaling, migration and differentiation, oxidative stress and the immune system. DPP4 is also expressed on the surface of osteoblasts, osteoclasts and osteocytes, and was found to play a role in collagen metabolism. Many substrates of DPP4 have an established role in bone metabolism, among which are incretins, gastrointestinal peptides and neuropeptides. In general, their effects favor bone formation, but some effects are complex and have not been completely elucidated. DPP4 and some of its substrates are known to interact with adipokines, playing an essential role in the energy metabolism. The prolongation of the half-life of incretins through DPP4 inhibition led to the development of these inhibitors to improve glucose tolerance in diabetes. Current literature indicates that the inhibition of DPP4 activity might also result in a beneficial effect on the bone metabolism, but the long-term effect of DPP4 inhibition on fracture outcome has not been entirely established. Diabetic as well as postmenopausal osteoporosis is associated with an increased activity of DPP4, as well as a shift in the expression levels of DPP4 substrates, their receptors, and adipokines. The interactions between these factors and their relationship in bone metabolism are therefore an interesting field of study.
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Affiliation(s)
- Lorenzo Glorie
- Laboratory of Pathophysiology, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
| | - Patrick C D'Haese
- Laboratory of Pathophysiology, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium
| | - Anja Verhulst
- Laboratory of Pathophysiology, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium
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50
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Schmeltzer SN, Herman JP, Sah R. Neuropeptide Y (NPY) and posttraumatic stress disorder (PTSD): A translational update. Exp Neurol 2016; 284:196-210. [PMID: 27377319 PMCID: PMC8375392 DOI: 10.1016/j.expneurol.2016.06.020] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Revised: 06/15/2016] [Accepted: 06/20/2016] [Indexed: 12/12/2022]
Abstract
Posttraumatic stress disorder (PTSD) is a trauma-evoked syndrome, with variable prevalence within the human population due to individual differences in coping and resiliency. In this review, we discuss evidence supporting the relevance of neuropeptide Y (NPY), a stress regulatory transmitter in PTSD. We consolidate findings from preclinical, clinical, and translational studies of NPY that are of relevance to PTSD with an attempt to provide a current update of this area of research. NPY is abundantly expressed in forebrain limbic and brainstem areas that regulate stress and emotional behaviors. Studies in rodents demonstrate a role for NPY in stress responses, anxiety, fear, and autonomic regulation, all relevant to PTSD symptomology. Genetic studies support an association of NPY polymorphisms with stress coping and affect. Importantly, cerebrospinal fluid (CSF) measurements in combat veterans provide direct evidence of NPY association with PTSD diagnosis and symptomology. In addition, NPY involvement in pain, depression, addiction, and metabolism may be relevant to comorbidities associated with PTSD. Collectively, the literature supports the relevance of NPY to PTSD pathophysiology, although knowledge gaps remain. The NPY system is an attractive target in terms of understanding the physiological basis of PTSD as well as treatment of the disorder.
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Affiliation(s)
- Sarah N Schmeltzer
- Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH 45237, United States
| | - James P Herman
- Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH 45237, United States
| | - Renu Sah
- Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH 45237, United States; VA Medical Center, Cincinnati, OH, 45220, United States.
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