Sclerostin in CKD-MBD: one more paradoxical bone protein?

Extract

Bone disease is frequently observed in chronic kidney disease (CKD) and increases a patient's risk for fracture, cardiovascular (CV) calcification and mortality. The Kidney Disease Improving Global Outcomes foundation defined a new syndrome incorporating the bone, mineral and CV disorders, such as chronic kidney disease–mineral and bone disorders (CKD–MBDs) [1]. The relationship between the bone turnover and CV disease is well documented in patients with CKD [2], as is the relationship between low bone density and aortic calcification in patients without CKD [3]. The quest for a modifiable reliable biomarker of CV and bone disease in CKD–MBD remains the nephrologist's Holy Grail. In recent years, numerous bone proteins have been associated with the outcome in patients with CKD, such as osteoprotegerin (OPG) [4], fibroblast growth factor (FGF)-23 [5], bone-specific alkaline phosphatase (bsALP) [6] and, more recently, sclerostin.

Sclerostin is a glycoprotein (22 kDa) product of the SOST gene in osteocytes, which inhibits osteoblast and bone formation. The canonical Wingless-type mouse mammary tumour virus integration site (Wnt) pathway has a bone anabolic and anti-catabolic effect. Sclerostin acts as an inhibitor of the Wnt-coreceptor LRP5/6. In the deep mineralized bone, osteocytes are able to detect mechanical strain, and when bone is subjected to mechanical forces, sclerostin is not secreted and bone formation occurs. Therefore, sclerostin appears to play an important role in the skeletal adaptation to mechanical forces [7]. Wnt signalling inhibits bone resorption and up-regulates OPG, which binds and inhibits the receptor activator of nuclear factor κB-ligand (RANKL) [8]. Patients with sclerosteosis or hyperostosis, who inherited high bone mass, were found to have a mutation of the SOST gene that impairs sclerostin activity [9]. Local parathyroid hormone (PTH) [10] and its administration reduces sclerostin expression in vivo [11]. Inversely, sclerostin production is increased by calcitonin. Sclerostin acts on osteoblasts in a paracrine manner, but little is known about possible endocrine action. Information on serum sclerostin kinetics with circadian or seasonal variations is lacking. Information on racial differences, factors influencing production and serum levels such as physical activity and nutrition, and the impact of different medications is scarce. However, longitudinal studies showed a relative serum sclerostin level stability.