Sclerostin Deficiency Is Linked to Altered Bone Composition

Abstract

High bone mass in animals and humans with sclerostin deficiency is associated with increased bone strength, which is not the case for all disorders with high bone mineral density, some of which are even associated with fragility fractures owing to unfavorable bone composition. In the current study we investigated whether alterations in bone composition may contribute to the bone strength characteristics associated with lack of sclerostin. We examined cortical bone of Sost-knockout (KO) mice (n ¼ 9, 16 weeks old) and sclerosteosis patients (young [4 to 14 years], n ¼ 4 and adults [24 and 43 years], n ¼ 2) by quantitative backscattered electron imaging and Raman microspectroscopy and compared it to bone from wild-type mice and healthy subjects, respectively. In Sost-KO mice endocortical bone exhibited altered bone composition, whereas subperiosteal bone was unchanged. When comparing endocortical bone tissue of identical tissue age as defined by sequential dual fluorochrome labeling the average bone matrix mineralization was reduced À1.9% (p < 0.0001, younger tissue age) and À1.5% (p < 0.05, older tissue age), and the relative proteoglycan content was significantly increased. Similarly, bone matrix mineralization density distribution was also shifted toward lower matrix mineralization in surgical samples of compact bone of sclerosteosis patients. This was associated with an increase in mineralization heterogeneity in the young population. In addition, and consistently, the relative proteoglycan content was increased. In conclusion, we observed decreased matrix mineralization and increased relative proteoglycan content in bone subcompartments of Sost-KO mice-a finding that translated into sclerosteosis patients. We hypothesize that the altered bone composition contributes to the increased bone strength of patients with sclerostin deficiency.

Bone Matrix Composition Following PTH Treatment is Not Dependent on Sclerostin Status

“…Sclerostin is a potent inhibitor of bone formation and recently it was shown to inhibit osteoblastic mineralization in vivo [2,22]. Our results show a reduction in the mineralto-matrix ratio in SOST KO animals compared to their wild-type controls, which is consistent with previous characterization of SOST deficient mice and human biopsies from patients with sclerostin mutations [9]. It is likely that this is due to the dramatically elevated bone formation rates noted in SOST KO animals [16,29].…”

“…It is interesting that the local FTIRM measurements found reduced mineral-to-matrix due to the SOST deficiency, but the global bSEM mineralization measurements did not show any evidence of depressed mineralization. This seeming discrepancy may suggest that the reduced mineralization is transient; although Hassler et al [9] noted that the reduced mineral-to-matrix ratio persists into tissue-ages of at least 65 days. Further, experiments are necessary to determine whether the maturation process is permanently impaired by SOST deficiency or whether there is a new peak tissue maturity level when sclerostin is absent.…”

Structural and functional insights into sclerostin-glycosaminoglycan interactions in bone

“…Wnt target genes that are affected by sclerostin include key regulators of osteoblast, osteoclast and osteocyte differentiation and function such as alkaline phosphatase, osteoprotegerin (OPG), connexin-43, and cyclooxygenase 2 [1,2]. The essential role of sclerostin for bone biology is highlighted by the fact that humans with inherited sclerostin deficiency display a generalized increase of bone mass and strength, which confers protection against fractures [3]. Previous studies employing antibodies against sclerostin resulted in a marked increase in bone mass and bone strength in rats and humans [4,5].…”

Effect of sclerostin removal <i>in vivo</i> on experimental periodontitis in mice

“…High sclerostin expression, resulting from inhibition of the WNT/betacatenin pathway, can induce bone resorption and reduce bone formation in patients with diseases such as osteoporosis (10). In contrast, sclerostin deficiency in patients with sclerosteosis and Van Buchem disease (11,12) (13). SOST, the gene for sclerostin, is located at position 11.2 on the long arm of chromosome 17.…”