Bone Abstracts

Chronic stress and depression are associated with alterations in the hypothalamic-pituitary-adrenal signalling 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. Utilising a transgenic (tg) mouse model in which glucocorticoid signalling is selectively disrupted in mature osteoblasts and osteocytes (HSD2^OB-tg mice), the current study examines the impact of chronic stress on skeletal metabolism and structure.

Eight-week-old male and female transgenic mice and their WT littermates were exposed to chronic mild stress for the duration of 4 weeks. Stressors included restraining, exposure to hot and cold, tilted cages and overnight illuminations. At endpoint, L3-vertebrae and tibiae were analysed by micro-CT and histomorphometry, blood was collected for markers of bone turnover.

Compared to the non-stressed controls, exposure to chronic stress resulted in loss of vertebral trabecular bone mass in male WT mice but not in HSD2^OB-tg male littermates (WT: −15.9% tg: +2.8%, P<0.05). Bone loss in mice with intact osteoblastic glucocorticoid signaling was due to a decrease in trabecular number (WT:−14.3% tg:+0.8%, P<0.01) and an increase in trabecular separation (WT:+12.1% tg:+1.2%, P<0.05). While trabecular bone in the tibia was unaffected in stress-exposed WT and HSD2^OB-tg males, tibial cortical area (WT: −11.1% tg:+1.3%, P<0.05) as well as cortical area fraction (WT: −9.5% tg: −2.6%, P=0.054) were reduced in stressed WT but not in stressed HSD2^OB-tg male mice. Histomorphometry and measurements of serum TRAP5b revealed an increase in osteoclast activity in WT males following stress exposure, an effect that was absent in HSD2^OB-tg males. Interestingly, in female mice, both vertebral and long bone structural parameters remained unaffected by chronic mild stress.

We conclude that in male mice, bone loss during chronic mild stress is mediated via glucocorticoid signalling in osteoblasts and subsequent activation of osteoclasts.