TRIM33 protects osteoblasts from oxidative stress-induced apoptosis in osteoporosis by inhibiting FOXO3a ubiquitylation and degradation.

This study aimed to probe into the effect of TRIM33 on oxidative stress-induced apoptosis of osteoblasts in osteoporosis and to probe into the underlying mechanism. The apoptosis of osteoblasts was induced by H2 O2 treatment and tested by flow cytometry. A mouse osteoporosis model was conducted by ovariectomy (OVX). The function of TRIM33 was assessed by in vitro and in vivo experiments. The mechanism of TRIM33 was determined by immunoprecipitation, immunofluorescent staining and co-transfection experiments. Here, we found that TRIM33 expression was lessened in the osteoblasts of patients with osteoporosis and was positively correlated with the bone mineral density of these patients. FOXO3a and TRIM33 were co-localized in the osteoblasts nuclei. TRIM33 silence boosted FOXO3a degradation in normal osteoblasts, while TRIM33 overexpression restrained FOXO3a degradation in H2 O2 -treated osteoblasts. The binding of TRIM33 to CBP and its overexpression restrained CBP-mediated FOXO3a acetylation, thereby attenuating FOXO3a ubiquitylation. The H2 O2 -induced apoptosis of osteoblasts was restrained by TRIM33 overexpression, while the FOXO3a knockdown reversed this trend. The in vivo experiments corroborated that TRIM33 overexpression attenuated the OVX-driven impacts in mice. In general, our findings expounded that TRIM33 protected osteoblasts against oxidative stress-induced apoptosis in osteoporosis and that the underlying mechanism was the restraint of FOXO3a ubiquitylation and degradation.

The association of XRCC1 polymorphism with osteosarcoma risk, clinicopathologic features, and prognosis in a Chinese Han population.

INTRODUCTION: The association of single-nucleotide polymorphisms at X-ray repair cross-complementing group-1 (XRCC1) with osteosarcoma (OS) development has not been fully clear to date. The aim of the present study is to evaluate the association of XRCC1 polymorphisms with risk, clinicopathologic features, and prognosis in Chinese OS patients. METHODS: A total of 146 patients with primary OS and 248 age- and gender-matched controls were included in the present study. The frequencies of four XRCC1 polymorphisms (rs25487, rs1799782, rs25489, and rs3213245) were determined between OS patients and controls. The association of XRCC1 polymorphism with clinicopathologic characteristics, prognosis, and XRCC1 expression was further evaluated. RESULTS: Compared with TT genotype, individuals carrying the minor C allele (TC+ CC) of rs3213245 had significantly increased risk of OS development (OR =1.83, 95% CI 1.14-3.00). OS patients carrying TC genotype and C allele at rs3213245 were more likely to be with larger tumor size and metastasis. Survival analysis demonstrated that OS patients carrying C allele (TC + CC) at rs3213245 had shorter survival time than those with TT genotype. The T to C substitution at rs3213245 could decrease XRCC1 gene transcriptional activity in vitro. XRCC1 mRNA and protein expression levels were lower in OS patients carrying TC or CC genotype at rs3213245. Besides, no significant association of rs25487, rs1799782, and rs25489 with OS was observed. CONCLUSION: In conclusion, these findings revealed that XRCC1 rs3213245 polymorphism was associated with increased risk of OS, which could affect XRCC1 expression in vitro and in vivo.