Hormonal and systemic regulation of sclerostin

Abstract

The Wnt/β-catenin signaling pathway plays an essential role in osteoblast biology. Sclerostin is a soluble antagonist of Wnt/β-catenin signaling secreted primarily by osteocytes. Current evidence indicates that sclerostin likely functions as a local/paracrine regulator of bone metabolism rather than as an endocrine hormone. Nonetheless, circulating sclerostin levels in humans often reflect changes in the bone microenvironment, although there may be exceptions to this observation. Using existing assays, circulating sclerostin levels have been shown to be altered in response to both hormonal stimuli and across a variety of normal physiological and pathophysiological conditions. In both rodents and humans, parathyroid hormone provided either intermittently or continuously suppresses sclerostin levels. Likewise, most evidence from both human and animal studies supports a suppressive effect of estrogen on sclerostin levels. Efforts to examine non-hormonal/systemic regulation of sclerostin have in general shown less consistent findings or have provided associations rather than direct interventional information, with the exception of mechanosensory studies which have consistently demonstrated increased sclerostin levels with skeletal unloading, and conversely decreases in sclerostin with enhanced skeletal loading. Herein, we will review the existent literature on both hormonal and non-hormonal/systemic factors which have been studied for their impact on sclerostin regulation.

A Prospective Cohort Study Showing No Association Between Serum Sclerostin Level and Mortality in Maintenance Hemodialysis Patients

“…Several clinical factors associated with sclerostin production and serum sclerostin levels have been identified other than renal dysfunction in non-CKD subjects, including age, BMI, diabetes, estrogen, and PTH [34,35]. Relevant to our result is the previous finding that estrogen was associated with serum sclerostin levels [36]. Since most of our MHD patients were postmenopausal and estrogen levels in postmenopausal women are lower than in men of a similar age, serum sclerostin levels may be lower in females than males.…”

Wnt signaling in bone, kidney, intestine, and adipose tissue and interorgan interaction in aging

“…As described above, SOST has emerged as an endocrine factor that regulates glucose and fat metabolism . Outside of the skeleton, SOST is present in the serum, supporting a circulating endocrine role . Circulating SOST increases progressively with age and the higher serum SOST levels found in elderly postmenopasual women are associated with a greater risk of hip fractures .…”

Regulation of Bone Metabolism by Sex Steroids

“…Given increasing evidence that sclerostin modulates not only bone formation, but also bone resorption (Tu et al 2015), these findings suggest that sclerostin may be in the pathway of estrogen action on bone, as shown further by the mouse models discussed later. Moreover, similar to the translation of RANKL inhibition to a new therapeutic, sclerostin inhibition using a humanized monoclonal antibody, romosozumab (Cosman et al 2016), results in a profound increase in bone formation and reduction in bone resorption in postmenopausal women, qualitatively similar to the pattern of changes in bone turnover induced by estrogen treatment (Drake and Khosla 2017). …”

“…There is also considerable evidence from human studies that estrogen regulates the production of the proposed inhibitor of Wnt signaling, sclerostin (Drake and Khosla 2017). A number of studies have shown that treatment of postmenopausal women with estrogen (Modder et al 2011a,b; Fujita et al 2014; Farr et al 2015) or with the selective ER modulator, raloxifene (Chung et al 2012), reduces circulating sclerostin levels using several different assays for sclerostin.…”