Regulation of plasma osteocalcin by corticosterone and norepinephrine during restraint stress.

Osteocalcin (OC), an extracellular calcium-binding protein of bone origin, is synthesized by osteoblasts and binds with high specificity to bone mineral crystals. A small, but relatively consistent portion of newly synthesized OC which is released to circulation has been well correlated with histological indices of osteoblastic activity. Synthesis of OC is regulated by numerous hormones including glucocorticoids. We previously reported that mild mental stressors such as cage change or cold exposure decreased rat plasma OC by up to 40% within 1 h. A similar response was induced in a time- and dose-related manner by injection of physiological levels of corticosterone (CS), the active glucocorticoid in rats. Prone immobilization by foot restraint of conscious rats for up to 2 h (IMMO) is a well-characterized model of classic "fight-or-flight" response. This model induces an immediate and prolonged elevation of CS, as well as the catecholamines epinephrine (E) and norepinephrine (NE). In marked contrast to milder stressors, immobilization induced an immediate increase of plasma OC, greater than 50% within 5-20 min, which returned toward normal after 2 h of restraint. Selective ablation of the hormones by adrenal medulectomy, adrenalectomy, or blockade of sympathetic ganglia did not abolish the initial rapid rise of plasma OC. Even before IMMO, plasma OC was increased by about 50% in the absence of sympathetic neural function or adrenal CS production. The presence of both CS and NE, but not E, was required to return plasma OC concentrations to basal levels. This strongly suggests interaction of CS and NE to regulate plasma OC and its release from bone. As expected, prior cold exposure lowered plasma OC, but did not abolish a subsequent increase in response to IMMO, nor did IMMO repeated daily for 7 days. The stimulus for the initial rapid elevation of OC is unknown, but likely to be of importance in the role OC plays in response to stress. Further investigation of the OC under mental stress should help to understand the function of this abundant and highly conserved bone protein.