Upregulated serum sclerostin level in the T2DM patients with femur fracture inhibits the expression of bone formation/remodeling-associated biomarkers via antagonizing Wnt signaling

摘要

OBJECTIVE: Bone formation/remodeling-associated biomarkers, such as osteocalcin, amino pro-peptide of type 1 collagen (P1NP) and CrossLaps (CTX) have been deregulated in type 2 diabetes mellitus (T2DM) patients. In particular, the T2DM-associated sclerostin markedly inhibits the bone formation, suppresses the osteoblast activity and downregulates the bone turnover. PATIENTS AND METHODS: In the present study, we examined the serum levels of sclerostin, osteocalcin, P1NP and CTX in the T2DM patients. We evaluated the regulation on osteocalcin, P1NP and CTX by sclerostin treatment in osteoblast hFOB 1.19 cells. Finally, we determined the mediation of Wnt signaling in the regulation by sclerostin on osteocalcin, P1NP and CTX in human osteoblast hFOB 1.19 cells. RESULTS: It was demonstrated that osteocalcin, P1NP and CTX were downregulated in the femur fracture of patients with T2DM, whereas the serum level of the sclerostin was markedly higher in the femur fracture of patients with T2DM. Moreover, the downregulated osteocalcin, P1NP or CTX was negatively associated with the upregulated sclerostin. In vitro results confirmed that sclerostin downregulated the expression of osteocalcin, P1NP and CTX in hFOB 1.19 cells. Also, our results demonstrated that Wnt/β-catenin inhibition was associated with the sclerostin-mediated inhibition of osteocalcin, P1NP and CTX in hFOB 1.19 cells. The Wnt/β-catenin level was markedly inhibited by sclerostin treatment, and the siRNA-mediated downregulation of β-catenin reduced the levels of osteocalcin, P1NP and CTX. CONCLUSIONS: Our study demonstrated that the upregulated serum sclerostin level in the T2DM patients with fracture inhibited the expression of the bone formation/remodeling-associated biomarkers via antagonizing Wnt signaling. It suggests that sclerostin might be an effective target for T2DM-associated bone fracture and delayed fracture healing.