Osteoporosis, an aging-associated bone metabolic disease, is affecting millions of people worldwide. The deregulated process of osteoblastic differentiation has been linked with the progression of osteoporosis. Trelagliptin is a long-acting inhibitor of DPP-4 used for the management of type 2 diabetes mellitus. However, it is unknown whether Trelagliptin possesses a beneficial effect in osteoblastic differentiation. Interestingly, we found that treatment with Trelagliptin enhanced differentiation and promoted the mineralization of MC3T3-E1 cells. Firstly, Trelagliptin increased the activity of alkaline phosphatase (ALP) and promoted osteoblastic calcium deposition. Additionally, treatment with Trelagliptin upregulated ALP, osteocalcin (OCN), osteopontin (OPN), and bone morphogenetic protein-2 (BMP-2). Notably, Trelagliptin increased RUNX2, a major regulator of osteoblastic differentiation. Mechanistically, Trelagliptin upregulated the levels of p-AMPKα. Blockage of AMPK with compound C abolished the effects of Trelagliptin in RUNX2 and osteoblastic differentiation, suggesting the involvement of AMPK. Our findings suggest that Trelagliptin might possess a potential for the treatment of osteoporosis.

ABSTRACT. We investigated the association between CASP-9 polymorphisms and susceptibility to neoplasm. Fourteen studies with a total of 2733 neoplasm cases and 3352 healthy controls were included. Meta-analysis showed that the rs4645981*T allele and the rs4645981*T allele carrier were positively associated with neoplasm susceptibility [odds ratio (OR) = 1.43, 95% confidence interval (95%CI) = 1.12-1.81, P = 0.004; OR = 1.46, 95%CI = 1.10-1.93, P = 0.009, respectively]. However, the rs1052576*A allele, rs1052576*A carrier, rs2308941*T allele, and rs2308941*T carrier might decrease the risk of cancer (OR = 0.72, 95%CI = 0.58-0.89, P = 0.003; OR = 0.76, 95%CI = 0.63-0.92, P = 0.004; OR = 0.20, 95%CI = 0.09-0.45, P < 0.0001; OR = 0.21, 95%CI = 0.06-0.75, P = 0.02, respectively). There was no significant association between rs1263, rs1052571, rs2308950, rs4645978, rs4645980, rs4645982, and rs4646018 and cancer risk (all P > 0.05). In conclusion, this meta-analysis suggests that CASP-9 gene polymorphisms are involved in the pathogenesis of various cancers. The rs4645981*T allele and the rs4645981*T allele carrier might increase the risk of cancer, but the rs1052576*A allele, rs1052576*A carrier, rs2308941*T allele, and rs2308941*T carrier might be protective.

ABSTRACT. The caspase (CASP) gene family is known to be involved in apoptosis, cytokine maturation, cell growth, and differentiation. A large number of single nucleotide polymorphisms (SNPs) in the CASP gene family have been increasingly recognized as important regulators in the development of lung cancer. However, this specific association is still controversial. In this Human Genome Epidemiology review and meta-analysis, we summarized the available evidence associating lung cancer with the CASP gene family. Seven studies, which included 1155 lung cancer cases and 1120 healthy controls, met the inclusion criteria and were included in our meta-analysis. In seven studies, 19 different SNPs have been studied in seven CASP genes, including CASP-1, -2, -5, -7, -8, -9, and -10. Meta-analysis results showed positive associations between heterozygote (A/G) of rs507879 in the CASP-5 gene, the T allele of rs12415607 in the CASP-7 gene, and the T allele and T carrier (C/T+T/T) of rs4645981 in the CASP-9 gene with lung cancer susceptibility [odds ratio (OR) = 1.83, 95% confidence interval (95%CI) = 1.07-3.12, P = 0.03; OR = 1.18, 95%CI = 1.02-1.37, P = 0.03; OR = 1.43, 95%CI = 1.12-1.81, P = 0.004; OR = 1.46, 95%CI = 1.10-1.93, P = 0.009; respectively]. However, we found that homozygote (G/G) of rs2227310 in the CASP-7 gene, del allele, heterozygote (ins/del), and del carrier (ins/del + del/del) of rs3834129 in CASP-8 could be protective factors for lung cancer (OR = 0.17, 95%CI = 0.14-0.21, P = 0.0003; OR = 0.83, 95%CI = 0.72-0.97, P = 0.02; OR = 0.74, 95%CI = 0.64-0.85, P < 0.0001; OR = 0.81, 95%CI = 0.71-0.93, P = 0.002; respectively). In conclusion, based on this meta-analysis, we suggest that SNPs in CASP-5, -7, -8, and -9 are associated with susceptibility to lung cancer.©FUNPEC

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