Sclerostin does not play a major role in the pathogenesis of skeletal complications in type 2 diabetes mellitus

Abstract

SummaryIn contrast to previously reported elevations in serum sclerostin levels in diabetic patients, the present study shows that the impaired bone microarchitecture and cellular turnover associated with type 2 diabetes mellitus (T2DM)-like conditions in ZDF rats are not correlated with changes in serum and bone sclerostin expression.IntroductionT2DM is associated with impaired skeletal structure and a higher prevalence of bone fractures. Sclerostin, a negative regulator of bone formation, is elevated in serum of diabetic patients. We aimed to relate changes in bone architecture and cellular activities to sclerostin production in the Zucker diabetic fatty (ZDF) rat.MethodsBone density and architecture were measured by micro-CT and bone remodelling by histomorphometry in tibiae and femurs of 14-week-old male ZDF rats and lean Zucker controls (n = 6/group).ResultsZDF rats showed lower trabecular bone mineral density and bone mass compared to controls, due to decreases in bone volume and thickness, along with impaired bone connectivity and cortical bone geometry. Bone remodelling was impaired in diabetic rats, demonstrated by decreased bone formation rate and increased percentage of tartrate-resistant acid phosphatase-positive osteoclastic surfaces. Serum sclerostin levels (ELISA) were higher in ZDF compared to lean rats at 9 weeks (+40 %, p < 0.01), but this difference disappeared as their glucose control deteriorated and by week 14, ZDF rats had lower sclerostin levels than control rats (−44 %, p < 0.0001). Bone sclerostin mRNA (qPCR) and protein (immunohistochemistry) were similar in ZDF, and lean rats at 14 weeks and genotype did not affect the number of empty osteocytic lacunae in cortical and trabecular bone.ConclusionT2DM results in impaired skeletal architecture through altered remodelling pathways, but despite altered serum levels, it does not appear that sclerostin contributes to the deleterious effect of T2DM in rat bone.

Levels of serum sclerostin, metabolic parameters, and periodontitis in ­postmenopausal women with diabetes

“…Although the aim of this study was to find a possible association between levels of sclerostin and periodontal disease, other variables were also investigated, but no significant correlations with sclerostin were found, which is in agreement with data described by Pereira et al. (2016) . Thus, it is not possible to affirm that sclerostin contributed to periodontal disease in either the diabetic or nondiabetic populations.…”

“…Studying the role of sclerostin in the pathogenesis of DM2 in rats, Pereira et al. (2016) concluded that DM2 has a harmful effect on the microarchitecture of cancellous and cortical bone due to the reduction in bone formation and increase in resorption. However, the data indicate that the changes in bone microarchitecture and turnover associated with DM2 in rats are not a consequence of sclerostin expression.…”

Normal bone density and trabecular bone score, but high serum sclerostin in congenital generalized lipodystrophy

“…A recent abstract suggests that there is no or little relationship between serum sclerostin and skeletal sclerostin in mice (Baldock- ASBMR abstract, 2016). Similarly, a recent study in diabetic rats suggested the sclerostin does not have a major role in skeletal alterations of T2D [29]. …”

Novel skeletal effects of glucagon-like peptide-1 (GLP-1) receptor agonists

“…Although an in vitro study reported an increased production of sclerostin by osteocyte-like cell line when cultured in hyperglycaemia (Tanaka et al 2015b, Pereira et al 2016), our recent study shows that the impaired bone microarchitecture and cellular turnover associated with T2DM-like conditions in diabetic ZDF rats are not correlated with changes in serum sclerostin levels, bone sclerostin expression or osteocyte viability (Pereira et al 2017). On the other hand, high fat diet in mice resulted in increased serum sclerostin and dramatic alterations of osteocyte network organisation (Mabilleau et al 2016).…”

“…Despite increased osteoblastogenesis, no direct effect of GLP-1RAs on bone nodule mineralisation in vitro was shown with up to 100 nM of exenatide and 1000 nM of liraglutide (Ma et al 2013, Pereira et al 2015. It is well established that exposure of primary osteoblast cells to high glucose levels inhibits in vitro bone nodule formation (Balint et al 2001, Pereira et al 2017. Interestingly, despite no effect of exenatide on bone formation in normal glucose conditions, unpublished results from our group demonstrate that it can reduce the deleterious effect of glucose on bone formation in vitro, in a dose-dependent manner.…”