Depression induces bone loss through stimulation of the sympathetic nervous system

Abstract

Major depression is associated with low bone mass and increased incidence of osteoporotic fractures. However, causality between depression and bone loss has not been established. Here, we show that mice subjected to chronic mild stress (CMS), an established model of depression in rodents, display behavioral depression accompanied by impaired bone mass and structure, as portrayed by decreases in trabecular bone volume density, trabecular number, and trabecular connectivity density assessed in the distal femoral metaphysis and L3 vertebral body. Bone remodeling analysis revealed that the CMS-induced skeletal deficiency is accompanied by restrained bone formation resulting from reduced osteoblast number. Antidepressant therapy, which prevents the behavioral responses to CMS, completely inhibits the decrease in bone formation and markedly attenuates the CMS-induced bone loss. The depression-triggered bone loss is associated with a substantial increase in bone norepinephrine levels and can be blocked by the ␤-adrenergic antagonist propranolol, suggesting that the sympathetic nervous system mediates the skeletal effects of stress-induced depression. These results define a linkage among depression, excessive adrenergic activity, and reduced bone formation, thus demonstrating an interaction among behavioral responses, the brain, and the skeleton, which leads to impaired bone structure. Together with the common occurrence of depression and bone loss in the aging population, the present data implicate depression as a potential major risk factor for osteoporosis and the associated increase in fracture incidence.antidepressant ͉ chronic depression ͉ osteoporosis ͉ bone formation ͉ adrenergic signaling

Chronic Psychological Stress as a Risk Factor of Osteoporosis

“…Therefore, gonadal hormones could be involved in mediating the stress-induced bone loss process. However, some animal and human studies reported that chronic stress-related low bone mass had the same normal estrogen and testosterone levels as the controls [35,40]. A potential interaction between gonadal hormone and stress-induced bone loss requires further investigation.…”

“…Animal experiments with chronic psychological stress also showed the loss of bone mass and deterioration of bone quality [14,40]. Mice were exposed to a regimen of stressors every day over a period of 4 to 5 weeks.…”

“…Several human studies report that blood cortisol levels were elevated in depressed patients, concomitantly with low BMD [41,42]. Animal studies also showed an elevation of the circulating corticosterone levels and adrenal weight, accompanied by lower bone quantity and bone quality in chronic stressed mice [14,40]. Chronic stress triggers the hy-pothalamus to release CRH, activates the HPA axis, and stimulates the secretion of GC.…”

“…Elevation of noradrenaline level was confirmed in chronic stress model animals along with bone loss. Furthermore, stress-triggered bone loss can be partially ameliorated by β-adrenergic antagonist propranolol, suggesting that the sympathetic nervous system mediates stress-induced bone loss [40]. Bone remodeling is controlled by the systemic and local endocrine system, including gonadal hormones [45].…”

Oleoyl serine, an endogenous N -acyl amide, modulates bone remodeling and mass

“…The skeletal activity of OS was analyzed by a combined μCT/histomorphometric system (11,47,48). Briefly, femora and L3 lumbar vertebrae were examined by a μCT system (μCT 40; Scanco Medical AG) at 20-μm resolution in all three spatial dimensions.…”