Chronic Mild Stress Causes Bone Loss via an Osteoblast-Specific Glucocorticoid-Dependent Mechanism

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.

Potential mechanisms linking psychological stress to bone health

“…Overall, the increased glucocorticoid level may lead to negative bone turnover and subsequently bone loss. This mechanism explains the report of Henneicke et al, whereby even chronic mild stress upregulates glucocorticoid signalling, which subsequently causes bone loss, in a site-and gender-specific manner [14].…”

“…Several studies have demonstrated that psychological stress is associated with osteoporosis [12][13][14][15][16]. Fink et al demonstrated that the number of stressful life events correlated positively with the risk of concurrent accelerated hip bone loss in older men [15].…”

The low‐expression programming of 11β‐HSD2 mediates osteoporosis susceptibility induced by prenatal caffeine exposure in male offspring rats

“…Meanwhile, prenatal caffeine exposure reduced the bone 11β‐HSD2 expression in male offspring before and after birth. Previous studies reported that the stable expression of 11β‐HSD2 in bone tissue can inactivate serum corticosterone and effectively regulate the bone corticosterone level to ensure the normal bone development (Henneicke et al, 2017; McNeil et al, 2007). So, these findings suggested that the continuously increased bone corticosterone was attributed to the reduced bone 11β‐HSD2 expression in prenatal caffeine exposure male offspring.…”

Crosstalk between Bone and Nerves within Bone

“…[ 251 ] The relationship between psychological stress and osteoporosis has been demonstrated with chronic mild stress, an established rodent model which leads to depression, causing reduction in osteoblast number, bone loss and reduced bone formation. [ 252,253 ] Peripheral nerves participate in regulating bone metabolism in individuals with psychological stress ( Figure A). One way in which psychological stress may impact osteoporotic disease risk and severity is through catecholamine‐induced activation of β ‐adrenergic receptors on osteoblasts and osteoclasts, which can increase RANKL expression and result in osteoclast differentiation.…”