Abstract
Sclerostin is a potent inhibitor of Wnt signaling and bone formation. However, there is currently no information on the relation of circulating sclerostin levels to age, gender, or bone mass in humans. Thus we measured serum sclerostin levels in a population-based sample of 362 women [123 premenopausal, 152 postmenopausal not on estrogen treatment (ET), and 87 postmenopausal on ET] and 318 men, aged 21 to 97 years. Sclerostin levels (mean ± SEM) were significantly higher in men than women (33.3 ± 1.0 pmol/L versus 23.7 ± 0.6 pmol/L, p < .001). In pre- and postmenopausal women not on ET combined (n = 275) as well as in men, sclerostin levels were positively associated with age (r = 0.52 and r = 0.64, respectively, p < .001 for both). Over life, serum sclerostin levels increased by 2.4- and 4.6-fold in the women and men, respectively. Moreover, for a given total-body bone mineral content, elderly subjects (age ≥ 60 years) had higher serum sclerostin levels than younger subjects (ages 20 to 39 years). Our data thus demonstrate that (1) men have higher serum sclerostin levels than women, (2) serum sclerostin levels increase markedly with age, and (3) compared with younger subjects, elderly individuals have higher serum sclerostin levels for a given amount of bone mass. Further studies are needed to define the cause of the age-related increase in serum sclerostin levels in humans as well as the potential role of this increase in mediating the known age-related impairment in bone formation. © 2011 American Society for Bone and Mineral Research.
Highlights
Given that sclerostin is produced almost exclusively by osteocytes,(1,3,5,6) this observation would be consistent with increased skeletal sclerostin production with aging in humans
Using total-body bone mineral content (TBBMC) as a surrogate for total skeletal mass, we found that while TBBMC was not associated with serum sclerostin levels in young women or men, TBBMC was positively associated with sclerostin levels in the elderly subjects of both sexes
Since sclerostin is a potent inhibitor of bone formation,(1,3) one might have predicted the opposite, namely, that serum sclerostin levels would be inversely associated with TBMMC
Summary
Considerable work over the past decade has established the Wnt/b-catenin signaling pathway as a major regulator of bone mass.[1,2] Activation of this pathway results in an expansion of osteoprogenitor cells as well as reduced apoptosis of mature osteoblasts, leading to increased bone formation and potentially marked increases in bone mass.[1,2] The effects of Wnt ligands on the canonical signaling pathway involving b-catenin signaling are mediated by binding of these ligands to a seven-transmembrane domain-spanning frizzled receptor and either of two coreceptors, low-density lipoprotein receptor–related proteins (LRP) 5 or 6.(1,2)Sclerostin is a secreted Wnt antagonist produced almost exclusively by osteocytes that regulates bone mass by binding to LRP5 and LRP6 to inhibit the canonical Wnt/b-catenin signaling pathway.[1,3,4,5,6] The biologic importance of sclerostin in humans is highlighted by sclerosteosis and van Buchem disease, two genetic diseases associated with markedly increased bone mass.[7,8,9,10] Sclerosteosis is caused by a mutation in the gene encoding sclerostin, SOST, that leads to improper splicing of the SOST mRNA,(7,8) whereas van Buchem disease is due to a deletion of an enhancer element downstream of the SOST gene.[9,10] In addition to these human diseases, mice with knockout of the Sost gene have increased bone-formation rates at trabecular, endocortical, and periosteal surfaces, as well as increased bone mass.[11]. Using an in-house Amgen immunoassay (Thousand Oaks, CA, USA), Mirza and colleagues[13] demonstrated that sclerostin could be measured in peripheral serum and was higher in 20 postmenopausal than in an equal number of premenopausal women. These investigators found that in the postmenopausal women there were significant negative correlations between sclerostin levels and the free estrogen (E) index and parathyroid hormone (PTH) levels. Given the availability of a validated immunoassay for sclerostin, we sought in this study to measure serum sclerostin levels in a population-based sample of women and men in order to define possible relations of sclerostin levels to age and gender, as well as bone mass, microstructure, sex steroid levels, and bone turnover markers
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