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.
Highlights
Bones are essential components of the musculoskeletal system and subjected to continuous remodeling as an adaptation mechanism to environmental changes
Gene expression analysis revealed that key receptors for nerve growth factors, neurotransmitters and neuropeptides (Figure 1) and selected receptors’ ligands (Figure 2) were changed in MSUS mice in a pattern that may promote higher bone turnover and lower bone density
MRNA expression of the receptors NPYR1 (p < 0.05, Figure 1B), VIPR1 (p < 0.001, Figure 1C) and TACR1 (p < 0.01, Figure 1D) were significantly reduced in MSUS mice whole bone homogenates, suggesting their presence on osteocytes. These three receptors are involved in the regulation of proliferation and differentiation in bone, and their concomitant downregulation may lead to higher remodeling activity with less proliferation and more differentiation of bone cells
Summary
Bones are essential components of the musculoskeletal system and subjected to continuous remodeling as an adaptation mechanism to environmental changes. Neurotrophic growth factors such as nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) that guide outgrowing nerve fibers to bony areas requiring innervation are of interest. Stress alters their expression, and they can act as direct and indirect growth factors for osteoblasts [14,15,16,17,18,19,20,21,22,23,24,25,26]. Latest studies indicate that psychosocial stress can lead to structural and functional changes in neuronal plasticity, neuronal marker expression, mitochondria and inflammation [4,27,28], possibly resulting in downstream alterations of bone homeostasis [29,30,31,32,33]
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