Sclerostin in Mineralized Matrices and van Buchem Disease

Abstract

Sclerostin is an inhibitor of bone formation expressed by osteocytes. We hypothesized that sclerostin is expressed by cells of the same origin and also embedded within mineralized matrices. In this study, we analyzed (a) sclerostin expression using immunohistochemistry, (b) whether the genomic defect in individuals with van Buchem disease (VBD) was associated with the absence of sclerostin expression, and (c) whether this was associated with hypercementosis. Sclerostin was expressed by cementocytes in mouse and human teeth and by mineralized hypertrophic chondrocytes in the human growth plate. In individuals with VBD, sclerostin expression was absent or strongly decreased in osteocytes and cementocytes. This was associated with increased bone formation, but no overt changes in cementum thickness. In conclusion, sclerostin is expressed by all 3 terminally differentiated cell types embedded within mineralized matrices: osteocytes, cementocytes, and hypertrophic chondrocytes.

Sclerostin antibody treatment enhances bone strength but does not prevent growth retardation in young mice treated with dexamethasone

“…Immunohistochemical analysis of the mouse femurs using Scl-AbI confirmed previous findings indicating that the osteocyte is the major cellular source of sclerostin in the mouse epiphysis ( Figure 1A). It was also clear that the basal layer of the articular cartilage contained a number of sclerostinpositive cells, which appeared to be hypertrophic chondrocytes, similar to observations recently reported in a study by van Bezooijen et al (25). Although the growth plate itself did not contain sclerostin-positive cells, there were nests of cells adjacent to the growth plate that were positive for sclerostin expression ( Figure 1B).…”

“…The immunohistologic findings described in the present study are consistent with those from previous studies describing sclerostin expression as being primarily osteocytic, but they also confirm a recent report describing sclerostin expression in cells in the vicinity of the growth plate (25). Based on the expression pattern of sclerostin and the large stature of individuals with a defective sclerostin gene, it has been postulated that sclerostin may help to regulate linear growth in humans (25). The results presented herein show that neutralization of sclerostin by monoclonal antibody treatment does not prevent DEXinduced inhibition of linear growth in mice.…”

“…In adolescent humans, sclerostin has been reported to be expressed by both osteocytes and mineralized hypertrophic chondrocytes in the growth plate. It has been speculated that sclerostin may play a role in regulating chondrocyte proliferation, and that this could explain the tall stature of patients with sclerosteosis (25).…”

APC mutations are associated with increased bone mineral density in patients with familial adenomatous polyposis

“…Sclerostin normally antagonizes the canonical Wnt signaling pathway by binding to the Wnt coreceptors LRP5 and LRP6. (37) The increase in sclerostin we observed therefore might be interpreted as a negative-feedback mechanism to prevent further bone mass accrual. This notion is in agreement with in vivo data indicating that heterozygous Apc min/þ mice display high sclerostin transcript levels in the tibia associated with increased BMD.…”

Sclerostin: A gem from the genome leads to bone-building antibodies

“…Van Buchem disease, another very rare, recessively inherited high-bone-mass disorder, was determined to be caused by a 52-kb deletion 35 kb downstream of SOST, (19,20) resulting in absence of postnatal sclerostin expression. (21,22) For osteoporosis pseudoglioma syndrome (OPPG), a recessively inherited low-bone-mass disease, loss-of-function mutations were found in a Wnt signaling coreceptor, the low-density lipoprotein receptor-PERSPECTIVE J JBMR …”