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

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/ß-catenin inhibition was associated with the sclerostin-mediated inhibition of osteocalcin, P1NP and CTX in hFOB 1.19 cells. The Wnt/ß-catenin level was markedly inhibited by sclerostin treatment, and the siRNA-mediated downregulation of ß-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.

Antifertility treating with long term gossypol.

PIP: In the 1974-86 period, gossypol acetate was taken as an antifertility measure by 16 men. The initial dose was 20 mg/day, with a maintenance dose of 40 mg/week. Antifertility efficacy was obtained in all 16 cases. Azoospermia persisted in 1 case where the gossypol had been taken for 8 years and discontinued for the past 2 1/2 years. Symptoms experienced in the first 2 weeks of gossypol acetate administration included dizziness, anorexia, nausea, fatigue, and stomach discomfort. Results of examinations of blood and urine; functions of the heart, liver, lung, and liver; electrolytes; external genitalia; and sexual performance were all in the normal range. Measurements of semen, plasma biochemistry, and endocrine changes also were within normal limits. However, in the 9 cases in which the average value of plasma testosterone was near the lower limit of normal, the average value of follicle-stimulating hormone was higher than normal and the testosterone/luteinizing hormone ratio was unusually low. Testis biopsy indicated that long-term gossypol treatment affected both germ cells and Sertoli cells. Leydig cells also demonstrated some damage. Gossypol acetate is, in general, considered an ideal male contraceptive because of its long-term effectiveness, reversibility, and lack of severe toxic side effects.^ieng