Endocrine Abstracts

The risk of bone fracture at most skeletal sites rises rapidly with age. Changes in bone mass account for only a small part of this increased risk - an additional factor is the progressive reduction in the ability to form new bone. This decrease in bone formation and increased fracture risk is reminiscent of changes seen with glucocorticoid excess, however, circulating corticosteroid levels do not change with age. We have proposed that local rather than circulating levels of corticosteroids are important for bone cell function and that local corticosteroid levels are regulated by the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). Human osteoblasts express 11beta-HSD1 and can generate the active glucocorticoid cortisol from cortisone. In data presented here we have used a large number of primary human osteoblast (hOB) cultures to assess the effects of age on 11beta-HSD expression and activity at different bone sites. HOB cells were generated from collagenase-digested trabecular bone chips obtained from orthopaedic specimens. Confluent cells were assayed for 11beta-HSD1 activity using 250nM cortisone along with tritiated tracer. Steroids generated were separated by TLC and conversion determined using a Bioscan TLC plate reader. In cultures derived from several skeletal sites 11beta-HSD1 activity increased significantly with age(r=0.58, n=18, p<0.01). This correlation was even stronger for cultures derived only from the calcaneous (r=0.87, p<0.001, n=15). A similar increase in expression of 11beta-HSD1 mRNA with age was suggested using real-time PCR (r=0.35, n=10) but this increase was not statistically significant.

Our data indicate that rising 11beta-HSD1 activity with age can lead to increased intracellular glucocorticoid levels. Thus age-related decreases in bone formation and increases in fracture risk may represent a localised form of glucocorticoid-induced osteoporosis. Consequently, strategies that reduce osteoblastic 11beta-HSD1 activity may attenuate the age-related increase in fracture risk.