Effects of Early Life Stress on Bone Homeostasis in Mice and Humans

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 on bone microarchitecture (μCT), metabolism (qPCR), and neuronal stress mediator expression (qPCR) and contrasted 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 micro-CT. 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.

[1]  M. Rose,et al.  Alterations in Bone Homeostasis and Microstructure Related to Depression and Allostatic Load , 2019, Psychotherapy and Psychosomatics.

[2]  Ming-gao Zhao,et al.  Predictable chronic mild stress promotes recovery from LPS-induced depression , 2019, Molecular Brain.

[3]  A. Larue,et al.  Impacts of Psychological Stress on Osteoporosis: Clinical Implications and Treatment Interactions , 2019, Front. Psychiatry.

[4]  J. Licinio,et al.  Short-term antidepressant treatment has long-lasting effects, and reverses stress-induced decreases in bone features in rats , 2019, Translational Psychiatry.

[5]  P. Mantyh,et al.  The Changing Sensory and Sympathetic Innervation of the Young, Adult and Aging Mouse Femur , 2018, Neuroscience.

[6]  Cheng-Ta Li,et al.  Post‐traumatic stress disorder and risk of osteoporosis: A nationwide longitudinal study , 2018, Stress and health : journal of the International Society for the Investigation of Stress.

[7]  Yunqing Kang,et al.  Effect of Brain-Derived Neurotrophic Factor on the Neurogenesis and Osteogenesis in Bone Engineering. , 2018, Tissue engineering. Part A.

[8]  G. Falgares,et al.  Childhood Maltreatment, Pathological Personality Dimensions, and Suicide Risk in Young Adults , 2018, Front. Psychol..

[9]  J. Eckert,et al.  Effects of new beta-type Ti-40Nb implant materials, brain-derived neurotrophic factor, acetylcholine and nicotine on human mesenchymal stem cells of osteoporotic and non osteoporotic donors , 2018, PloS one.

[10]  B. McEwen,et al.  Psychological Stress and Mitochondria: A Conceptual Framework , 2018, Psychosomatic medicine.

[11]  E. Epel,et al.  An energetic view of stress: Focus on mitochondria , 2018, Frontiers in Neuroendocrinology.

[12]  E. Conte,et al.  Evaluation of Short and Long Term Cold Stress Challenge of Nerve Grow Factor, Brain-Derived Neurotrophic Factor, Osteocalcin and Oxytocin mRNA Expression in BAT, Brain, Bone and Reproductive Tissue of Male Mice Using Real-Time PCR and Linear Correlation Analysis , 2018, Front. Physiol..

[13]  Xiao-Feng Chen,et al.  Genetics association study and functional analysis on osteoporosis susceptibility gene BDNF. , 2017, Yi chuan = Hereditas.

[14]  S. Lupien,et al.  Early child adversity and psychopathology in adulthood: HPA axis and cognitive dysregulations as potential mechanisms , 2017, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[15]  Gisela Kuhn,et al.  Stress and Alterations in Bones: An Interdisciplinary Perspective , 2017, Front. Endocrinol..

[16]  Qian Yang,et al.  NPY and CGRP Inhibitor Influence on ERK Pathway and Macrophage Aggregation during Fracture Healing , 2017, Cellular Physiology and Biochemistry.

[17]  Yong-gang Li,et al.  Analysis of the mechanism by which nerve growth factor promotes callus formation in mice with tibial fracture , 2017, Experimental and therapeutic medicine.

[18]  M. Lamghari,et al.  Bone Injury and Repair Trigger Central and Peripheral NPY Neuronal Pathways , 2016, PloS one.

[19]  Lei-Sheng Jiang,et al.  Inhibition of substance P signaling aggravates the bone loss in ovariectomy-induced osteoporosis. , 2016, Progress in biophysics and molecular biology.

[20]  Li-ren Han,et al.  Substance P Promotes the Proliferation, but Inhibits Differentiation and Mineralization of Osteoblasts from Rats with Spinal Cord Injury via RANKL/OPG System , 2016, PloS one.

[21]  E. Conte,et al.  Nerve Growth Factor, Brain-Derived Neurotrophic Factor and Osteocalcin Gene Relationship in Energy Regulation, Bone Homeostasis and Reproductive Organs Analyzed by mRNA Quantitative Evaluation and Linear Correlation Analysis , 2016, Front. Physiol..

[22]  Labchan Rajbhandari,et al.  NGF-TrkA Signaling by Sensory Nerves Coordinates the Vascularization and Ossification of Developing Endochondral Bone. , 2016, Cell reports.

[23]  K. Tabeta,et al.  Neuronal TRPV1 activation regulates alveolar bone resorption by suppressing osteoclastogenesis via CGRP , 2016, Scientific Reports.

[24]  N. Maffulli,et al.  Chronic Psychosocial Stress Impairs Bone Homeostasis: A Study in the Social Isolation Reared Rat , 2016, Front. Pharmacol..

[25]  F. Coluzzi,et al.  Bone pain mechanism in osteoporosis: a narrative review. , 2016, Clinical cases in mineral and bone metabolism : the official journal of the Italian Society of Osteoporosis, Mineral Metabolism, and Skeletal Diseases.

[26]  M. Berk,et al.  Depression as a risk factor for fracture in women: A 10 year longitudinal study. , 2016, Journal of affective disorders.

[27]  M. Kaess,et al.  Associations between depression and specific childhood experiences of abuse and neglect: A meta-analysis. , 2016, Journal of affective disorders.

[28]  K. Kubo,et al.  Chronic Psychological Stress as a Risk Factor of Osteoporosis. , 2015, Journal of UOEH.

[29]  J. Ong,et al.  Beta-nerve growth factor promotes neurogenesis and angiogenesis during the repair of bone defects , 2015, Neural regeneration research.

[30]  A. Boskey,et al.  Osteoblast function and bone histomorphometry in a murine model of Rett syndrome. , 2015, Bone.

[31]  K. Jiao,et al.  Norepinephrine Regulates Condylar Bone Loss via Comorbid Factors , 2015, Journal of dental research.

[32]  W.H. Ma,et al.  Neuropeptide Y, substance P, and human bone morphogenetic protein 2 stimulate human osteoblast osteogenic activity by enhancing gap junction intercellular communication , 2015, Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas.

[33]  U. Gieler,et al.  Suitability of Nicotinic Acetylcholine Receptor α7 and Muscarinic Acetylcholine Receptor 3 Antibodies for Immune Detection , 2015, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[34]  I. Mansuy,et al.  Hippocampal gene expression induced by cold swim stress depends on sex and handling , 2015, Psychoneuroendocrinology.

[35]  A. Sophocleous,et al.  Rodent models of osteoporosis. , 2014, BoneKEy reports.

[36]  S. Grässel,et al.  The role of peripheral nerve fibers and their neurotransmitters in cartilage and bone physiology and pathophysiology , 2014, Arthritis Research & Therapy.

[37]  A. Zengin,et al.  Neuropeptide Y Attenuates Stress‐Induced Bone Loss Through Suppression of Noradrenaline Circuits , 2014, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[38]  Huayue Chen,et al.  Chewing ameliorates chronic mild stress-induced bone loss in senescence-accelerated mouse (SAMP8), a murine model of senile osteoporosis , 2014, Experimental Gerontology.

[39]  Bruce S. McEwen,et al.  Mitochondrial allostatic load puts the 'gluc' back in glucocorticoids , 2014, Nature Reviews Endocrinology.

[40]  L. Farinelli,et al.  Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice , 2014, Nature Neuroscience.

[41]  M. Weisskopf,et al.  Sexual and physical abuse in childhood is associated with depression and anxiety over the life course: systematic review and meta-analysis , 2014, International Journal of Public Health.

[42]  M. Lamghari,et al.  Neuropeptide Y modulates fracture healing through Y1 receptor signaling , 2013, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[43]  Y. Yau,et al.  Stress and eating behaviors. , 2013, Minerva endocrinologica.

[44]  J. Li,et al.  Serum EGF and NGF levels of patients with brain injury and limb fracture. , 2013, Asian Pacific journal of tropical medicine.

[45]  E. Brähler,et al.  Der Childhood Trauma Screener (CTS) – Entwicklung und Validierung von Schwellenwerten zur Klassifikation , 2013, Psychiatrische Praxis.

[46]  L. Williams,et al.  The Long-Term Impact of Early Adversity on Late-Life Psychiatric Disorders , 2013, Current Psychiatry Reports.

[47]  M. Lamghari,et al.  Neuropeptide Y Y1 receptor antagonism increases bone mass in mice. , 2012, Bone.

[48]  A. Terreni,et al.  Biochemical markers in the follow-up of the osteoporotic patients. , 2012, Clinical cases in mineral and bone metabolism : the official journal of the Italian Society of Osteoporosis, Mineral Metabolism, and Skeletal Diseases.

[49]  U. John,et al.  [A brief instrument for the assessment of childhood abuse and neglect: the childhood trauma screener (CTS)]. , 2012, Psychiatrische Praxis.

[50]  K. Obata,et al.  Age-related changes in afferent responses in sensory neurons to mechanical stimulation of osteoblasts in coculture system. , 2012, American journal of physiology. Cell physiology.

[51]  C. Nemeroff,et al.  Etiology of depression: genetic and environmental factors. , 2012, The Psychiatric clinics of North America.

[52]  T. Guo,et al.  Neuropeptide deficient mice have attenuated nociceptive, vascular, and inflammatory changes in a tibia fracture model of complex regional pain syndrome , 2012, Molecular pain.

[53]  U. Lerner,et al.  The neuropeptide VIP regulates the expression of osteoclastogenic factors in osteoblasts , 2011, Journal of cellular biochemistry.

[54]  A. Beck,et al.  Beck Depression Inventory–II , 2011 .

[55]  A. Danese,et al.  Childhood maltreatment predicts unfavorable course of illness and treatment outcome in depression: a meta-analysis. , 2011, The American journal of psychiatry.

[56]  Kozo Nakamura,et al.  Biochemical markers of bone turnover as predictors of osteoporosis and osteoporotic fractures in men and women: 10-year follow-up of the Taiji cohort , 2011, Modern rheumatology.

[57]  Richard J. K. Taylor,et al.  RANKL-independent human osteoclast formation with APRIL, BAFF, NGF, IGF I and IGF II. , 2011, Bone.

[58]  C. Cooper,et al.  Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards , 2011, Osteoporosis International.

[59]  C. Nemeroff,et al.  Neurobiological and psychiatric consequences of child abuse and neglect. , 2010, Developmental psychobiology.

[60]  A. Stark,et al.  Neuropeptide Y innervation during fracture healing and remodeling , 2010, Acta orthopaedica.

[61]  Holger Russig,et al.  Epigenetic Transmission of the Impact of Early Stress Across Generations , 2010, Biological Psychiatry.

[62]  Ralph Müller,et al.  Guidelines for assessment of bone microstructure in rodents using micro–computed tomography , 2010, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[63]  Patrick O. McGowan,et al.  The epigenetics of social adversity in early life: Implications for mental health outcomes , 2010, Neurobiology of Disease.

[64]  G. Csako,et al.  Depression and Osteoporosis: A Research Synthesis with Meta-Analysis , 2010, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[65]  M. Schmidt.  Molecular mechanisms of early life stress—Lessons from mouse models , 2010, Neuroscience & Biobehavioral Reviews.

[66]  C. Spitzer,et al.  Die deutsche Version des Childhood Trauma Questionnaire (CTQ): Erste Befunde zu den psychometrischen Kennwerten , 2010 .

[67]  T. Bale,et al.  Sex differences in the serotonergic influence on the hypothalamic-pituitary-adrenal stress axis. , 2010, Endocrinology.

[68]  S. Boonen,et al.  Sexual dimorphism in cortical bone size and strength but not density is determined by independent and time‐specific actions of sex steroids and IGF‐1: Evidence from pubertal mouse models , 2010, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[69]  L. Dai,et al.  Changes of substance P during fracture healing in ovariectomized mice , 2010, Regulatory Peptides.

[70]  Xi Jiang,et al.  Neuropeptide Y is expressed by osteocytes and can inhibit osteoblastic activity , 2009, Journal of cellular biochemistry.

[71]  Tomoaki Tanaka,et al.  cAMP activation by PACAP/VIP stimulates IL‐6 release and inhibits osteoblastic differentiation through VPAC2 receptor in osteoblastic MC3T3 cells , 2009, Journal of cellular physiology.

[72]  M. Sousa,et al.  NPY revealed as a critical modulator of osteoblast function in vitro: New insights into the role of Y1 and Y2 receptors , 2009, Journal of cellular biochemistry.

[73]  Martin Schmelz,et al.  Post-junctional facilitation of Substance P signaling in a tibia fracture rat model of complex regional pain syndrome type I , 2009, PAIN®.

[74]  C. Jacobs,et al.  Substance P stimulates bone marrow stromal cell osteogenic activity, osteoclast differentiation, and resorption activity in vitro. , 2009, Bone.

[75]  B. McEwen,et al.  Neuroscience, molecular biology, and the childhood roots of health disparities: building a new framework for health promotion and disease prevention. , 2009, JAMA.

[76]  Eun-Cheol Kim,et al.  Effects of substance P on osteoblastic differentiation and heme oxygenase‐1 in human periodontal ligament cells , 2009, Cell biology international.

[77]  J. Eisman,et al.  Critical Interplay Between Neuropeptide Y and Sex Steroid Pathways in Bone and Adipose Tissue Homeostasis , 2009, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[78]  T. Guo,et al.  Effect of anti-NGF antibodies in a rat tibia fracture model of complex regional pain syndrome type I , 2008, PAIN.

[79]  U. Lerner,et al.  Osteotropic effects by the neuropeptides calcitonin gene-related peptide, substance P and vasoactive intestinal peptide. , 2008, Journal of musculoskeletal & neuronal interactions.

[80]  S. Hendrix,et al.  Skin and hair follicle innervation in experimental models: a guide for the exact and reproducible evaluation of neuronal plasticity , 2008, Experimental dermatology.

[81]  C. Nemeroff,et al.  The Dexamethasone/Corticotropin-Releasing Factor Test in Men with Major Depression: Role of Childhood Trauma , 2008, Biological Psychiatry.

[82]  T. Goto,et al.  Substance P stimulates late-stage rat osteoblastic bone formation through neurokinin-1 receptors , 2007, Neuropeptides.

[83]  I. Goshen,et al.  Depression induces bone loss through stimulation of the sympathetic nervous system , 2006, Proceedings of the National Academy of Sciences.

[84]  R. Müller,et al.  Compartmental Bone Morphometry in the Mouse Femur: Reproducibility and Resolution Dependence of Microtomographic Measurements , 2005, Calcified Tissue International.

[85]  I. Katz,et al.  The role of stress-induced cortisol in the relationship between depression and decreased bone mineral density , 2005, Biological Psychiatry.

[86]  Shigeru Kobayashi,et al.  Neuropeptide substance P stimulates the formation of osteoclasts via synovial fibroblastic cells. , 2005, Biochemical and biophysical research communications.

[87]  S. Sohn.  Substance P upregulates osteoclastogenesis by activating nuclear factor kappa B in osteoclast precursors , 2005, Acta oto-laryngologica.

[88]  T. Nagata,et al.  Substance P enhances the inhibition of osteoblastic cell differentiation induced by lipopolysaccharide from Porphyromonas gingivalis. , 2004, Journal of periodontology.

[89]  M. Davies,et al.  A substance P receptor (NK1) antagonist enhances the widespread osteoporotic effects of sciatic nerve section. , 2003, Bone.

[90]  R. Eastell,et al.  Relationship of Early Changes in Bone Resorption to the Reduction in Fracture Risk With Risedronate , 2003, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[91]  F. Morvan,et al.  Chemical sympathectomy‐induced changes in TH‐, VIP‐, and CGRP‐immunoreactive fibers in the rat mandible periosteum: Influence on bone resorption , 2003, Journal of cellular physiology.

[92]  P. Mantyh,et al.  Origins of skeletal pain: sensory and sympathetic innervation of the mouse femur , 2002, Neuroscience.

[93]  Sharmila Majumdar,et al.  Changes in Bone Structure and Mass With Advancing Age in the Male C57BL/6J Mouse , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[94]  M. Longaker,et al.  A Mouse Model of Mandibular Osteotomy Healing , 2001, The Journal of craniofacial surgery.

[95]  Z. Dąbrowski,et al.  Effect of the neuropeptide substance P on the rat bone marrow‐derived osteogenic cells in vitro , 2001, Journal of cellular biochemistry.

[96]  U. Lerner,et al.  Microisolated mouse osteoclasts express VIP-1 and PACAP receptors. , 2000, Biochemical and biophysical research communications.

[97]  P. Delmas,et al.  Biochemical Markers of Bone Turnover, Endogenous Hormones and the Risk of Fractures in Postmenopausal Women: The OFELY Study , 2000, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[98]  K. Kataoka,et al.  Substance P regulates the function of rabbit cultured osteoclast; increase of intracellular free calcium concentration and enhancement of bone resorption. , 1999, Biochemical and biophysical research communications.

[99]  R. Flavell,et al.  Targeted Expression of Calcitonin Gene‐Related Peptide to Osteoblasts Increases Bone Density in Mice , 1999, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[100]  T. Tanaka,et al.  Light- and electron-microscopic study of the distribution of axons containing substance P and the localization of neurokinin-1 receptor in bone , 1998, Cell and Tissue Research.

[101]  C. Shih,et al.  Neurogenic Substance P Stimulates Osteogenesis In Vitro , 1997, Peptides.

[102]  A. R. Ward,et al.  Topical application of nerve growth factor improves fracture healing in rats , 1997, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[103]  K. Tamai,et al.  Substance P- and calcitonin gene-related peptide-immunofluorescent nerves in the repair of experimental bone defects , 1994, International Orthopaedics.

[104]  M. Hosokawa,et al.  Senescence‐Accelerated Mouse (SAM): A Novel Murine Model of Accelerated Senescence , 1991, Journal of the American Geriatrics Society.

[105]  B. McEwen,et al.  Stress Effects on Neuronal Structure: Hippocampus, Amygdala, and Prefrontal Cortex , 2016, Neuropsychopharmacology.

[106]  K. Geue,et al.  Diagnostische Verfahren in der Psychotherapie , 2016 .

[107]  He Ji-ye,et al.  Autonomic control of bone formation: its clinical relevance. , 2013, Handbook of clinical neurology.

[108]  Rajita Sinha,et al.  The Effects of Stress on Physical Activity and Exercise , 2013, Sports Medicine.

[109]  Johannes Bohacek,et al.  Epigenetic Inheritance of Disease and Disease Risk , 2013, Neuropsychopharmacology.

[110]  R. Muche,et al.  Medizinische Statistik mit R und Excel , 2011 .

[111]  Franz Petermann,et al.  Beck-Depressions-Inventar Revision (BDI–II) , 2010 .

[112]  C. Spitzer,et al.  [The German version of the Childhood Trauma Questionnaire (CTQ): preliminary psychometric properties]. , 2010, Psychotherapie, Psychosomatik, medizinische Psychologie.

[113]  W. Eaton,et al.  Depression and osteoporosis: epidemiology and potential mediating pathways , 2007, Osteoporosis International.

[114]  P. Lehenkari,et al.  Vasoactive Intestinal Peptide (VIP)/Pituitary Adenylate Cyclase-Activating Peptide Receptor Subtypes in Mouse Calvarial Osteoblasts: Presence of VIP-2 Receptors and Differentiation-Induced Expression of VIP-1 Receptors * * The present study was supported by grants from the Swedish Medical Research C , 2001, Endocrinology.

[115]  P. Lehenkari,et al.  Vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating peptide receptor subtypes in mouse calvarial osteoblasts: presence of VIP-2 receptors and differentiation-induced expression of VIP-1 receptors. , 2001, Endocrinology.