Thioredoxin Interacting Protein Expressed in Osteoblasts Mediates the Anti-Proliferative Effects of High Glucose and Modulates the Expression of Osteocalcin
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Background: Hyperglycemia is associated with impaired bone health in patients with diabetes mellitus. Although a direct detrimental effect of hyperglycemia on the bone has been previously reported, the specific molecular mediator(s) responsible for the inhibitory effect of high glucose levels on the bone remains unclear. We hypothesized that thioredoxin-interacting protein (Txnip), an essential mediator of oxidative stress, is such a mediator. Methods: We cultured MG-63 cells (immortalized human osteoblasts) with normal or high glucose concentrations and transfected them with scrambled or Txnip-specific small interfering RNA (siRNA). Results: High glucose levels increased Txnip expression and reduced MG-63 cell proliferation. The high-glucose level mediated reduction in cell proliferation was prevented in Txnip siRNA-transfected cells. In addition, we demonstrated that silencing Txnip mRNA expression in osteoblasts reduced the expression of the osteocalcin gene. Our results suggest that high glucose levels or silencing of Txnip mRNA expression may induce apoptosis in osteoblasts. Conclusions: Our findings indicate that Txnip is an intracellular mediator of the anti-proliferative effects of extracellular high glucose levels on osteoblasts.
Abstract
Background: Hyperglycemia is associated with impaired bone health in patients with diabetes mellitus. Although a direct detrimental effect of hyperglycemia on the bone has been previously reported, the specific molecular mediator(s) responsible for the inhibitory effect of high glucose levels on the bone remains unclear. We hypothesized that thioredoxin-interacting protein (Txnip), an essential mediator of oxidative stress, is such a mediator. Methods: We cultured MG-63 cells (immortalized human osteoblasts) with normal or high glucose concentrations and transfected them with scrambled or Txnip-specific small interfering RNA (siRNA). Results: High glucose levels increased Txnip expression and reduced MG-63 cell proliferation. The high-glucose level mediated reduction in cell proliferation was prevented in Txnip siRNA-transfected cells. In addition, we demonstrated that silencing Txnip mRNA expression in osteoblasts reduced the expression of the osteocalcin gene. Our results suggest that high glucose levels or silencing of Txnip mRNA expression may induce apoptosis in osteoblasts. Conclusions: Our findings indicate that Txnip is an intracellular mediator of the anti-proliferative effects of extracellular high glucose levels on osteoblasts.
참고문헌 (42)
- Wu Y, "Risk factors contributing to type 2 diabetes and recent advances in the treatment and prevention", Int J Med Sci, 11, pp.1185~1200 (2014)[DOI]
- Kanazawa I, "Diabetes mellitus-induced bone fragility", Intern Med, 57, pp.2773~2785 (2018)[DOI]
- Farr JN, "In vivo assessment of bone quality in postmenopausal women with type 2 diabetes", J Bone Miner Res, 29, pp.787~795 (2014)[DOI]
- Dong K, "Alpha-lipoic acid alleviates high-glucose suppressed osteogenic differentiation of MC3T3-E1 cells via antioxidant effect and PI3K", Akt signaling pathway, 2017, pp.42, 1897~1906
- Ogawa N, "The combination of high glucose and advanced glycation end-products(AGEs)inhibits the mineralization of osteoblastic MC3T3-E1 cells through glucose-induced increase in the receptor for AGEs", Horm Metab Res, 39, pp.871~875 (2007)[DOI]
- Medeiros C, "High glucose-induced inhibition of osteoblast like MC3T3-E1 differentiation promotes mitochondrial perturbations", PLoS One, 17, pp.e0270001~ (2022)[DOI]
- Yang J, "High glucose inhibits osteogenic differentiation and proliferation of MC3T3‑E1 cells by regulating P2X7", Mol Med Rep, 20, pp.5084~5090 (2019)[DOI]
- Cunha JS, "Effects of high glucose and high insulin concentrations on osteoblast function in vitro", Cell Tissue Res, 358, pp.249~256 (2014)[DOI]
- Manolagas SC, "From estrogen-centric to aging and oxidative stress : a revised perspective of the pathogenesis of osteoporosis", Endocr Rev, 31, pp.266~300 (2010)[DOI]
- Nishinaka Y, "Importin alpha1(Rch1)mediates nuclear translocation of thioredoxin-binding protein-2", vitamin D(3)-up-regulated protein 1, 2004, pp.279, 37559~37565
- Kobayashi T, "Vitamin D3 up-regulated protein-1 regulates collagen expression in mesangial cells", Kidney Int, 64, pp.1632~1642 (2003)[DOI]
- Hamada Y, "Thioredoxin-1 overexpression in transgenic mice attenuates streptozotocin-induced diabetic osteopenia : a novel role of oxidative stress and therapeutic implications", Bone, 44, pp.936~941 (2009)[DOI]
- Liang Y, "1, 25-Dihydroxy vitamin D3 treatment attenuates osteopenia, and improves bone muscle quality in Goto-Kakizaki type 2 diabetes model rats", Endocrine, 64, pp.184~195 (2019)[DOI]
- Vestergaard P, "Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes--a meta-analysis", Osteoporos Int, 18, pp.427~444 (2007)[DOI]
- Faienza MF, "Type 2 diabetes and bone fragility in children and adults", World J Diabetes, 13, pp.900~911 (2022)[DOI]
- Kurra S, "Diabetes and bone health : the relationship between diabetes and osteoporosis-associated fractures", Diabetes Metab Res Rev, 27, pp.430~435 (2011)[DOI]
- Bonds DE, "Risk of fracture in women with type 2 diabetes : the Women's Health Initiative Observational Study", J Clin Endocrinol Metab, 91, pp.3404~3410 (2006)[DOI]
- Ma L, "Association between bone mineral density and type 2 diabetes mellitus : a meta-analysis of observational studies", Eur J Epidemiol, 27, pp.319~332 (2012)[DOI]
- Leslie WD, "TBS(trabecular bone score)and diabetes-related fracture risk", J Clin Endocrinol Metab, 98, pp.602~609 (2013)[DOI]
- Ivers RQ, "Diabetes and risk of fracture : the Blue Mountains Eye Study", Diabetes Care, 24, pp.1198~1203 (2001)[DOI]
- Oei L, "High bone mineral density and fracture risk in type 2 diabetes as skeletal complications of inadequate glucose control : the Rotterdam Study", Diabetes Care, 36, pp.1619~1628 (2013)[DOI]
- Puar TH, "Association between glycemic control and hip fracture", J Am Geriatr Soc, 60, pp.1493~1497 (2012)[DOI]
- Li CI, "Glycated hemoglobin level and risk of hip fracture in older people with type 2 diabetes : a competing risk analysis of Taiwan diabetes cohort study", J Bone Miner Res, 30, pp.1338~1346 (2015)[DOI]
- Dufour AB, "Risk factors for incident fracture in older adults with type 2 diabetes : the framingham heart study", Diabetes Care, 44, pp.1547~1555 (2021)[DOI]
- Terada M, "Growth-inhibitory effect of a high glucose concentration on osteoblast-like cells", Bone, 22, pp.17~23 (1998)[DOI]
- Zhang P, "High glucose promotes apoptosis and autophagy of MC3T3-E1 osteoblasts", Arch Med Sci, 19, pp.138~150 (2023)[DOI]
- Li YM, "Effects of high glucose on mesenchymal stem cell proliferation and differentiation", Biochem Biophys Res Commun, 363, pp.209~215 (2007)[DOI]
- Jiang N, "Thioredoxin-interacting protein : a new therapeutic target in bone metabolism disorders?", Front Immunol, 13, pp.955128~ (2022)[DOI]
- Minn AH, "Thioredoxin-interacting protein is stimulated by glucose through a carbohydrate response element and induces beta-cell apoptosis", Endocrinology, 146, pp.2397~2405 (2005)[DOI]
- Choi EH, "TXNIP : a key protein in the cellular stress response pathway and a potential therapeutic target", Exp Mol Med, 55, pp.1348~1356 (2023)[DOI]
- Parikh H, "TXNIP regulates peripheral glucose metabolism in humans", PLoS Med, 4, pp.e158~ (2007)[DOI]
- Xu W, "TXNIP mediated the oxidative stress response in glomerular mesangial cells partially through AMPK pathway", Biomed Pharmacother, 107, pp.785~792 (2018)[DOI]
- Turturro F, "Hyperglycemia-induced thioredoxin-interacting protein expression differs in breast cancer-derived cells and regulates paclitaxel IC50", Clin Cancer Res, 13, pp.3724~3730 (2007)[DOI]
- Lekva T, "TXNIP is highly regulated in bone biopsies from patients with endogenous Cushing’s syndrome and related to bone turnover", Eur J Endocrinol, 166, pp.1039~1048 (2012)[DOI]
- Mo Y, "TXNIP contributes to bone loss via promoting the mitochondrial oxidative phosphorylation during glucocorticoid-induced osteoporosis", Life Sci, 266, pp.118938~ (2021)[DOI]
- Gu Y, "Knockdown of TXNIP alleviates gestational diabetes mellitus by activating autophagy to regulate cell proliferation and apoptosis in high glucose-treated trophoblasts", Reprod Biol, 24, pp.100841~ (2024)[DOI]
- Xu S, "Blocking TXNIP reduced IL-1β Induced chondrocyte cell inflammation", Cell Mol Biol(Noisy-le-grand), 69, pp.174~179 (2023)[DOI]
- Wang JS, "Sclerostin and osteocalcin : candidate bone-produced hormones", Front Endocrinol(Lausanne), 12, pp.584147~ (2021)[DOI]
- Ducy P, "Increased bone formation in osteocalcin-deficient mice", Nature, 382, pp.448~452 (1996)[DOI]
- Karsenty G, "Osteocalcin : a multifaceted bone-derived hormone", Annu Rev Nutr, 43, pp.55~71 (2023)[DOI]
- Kover K, "Osteocalcin protects pancreatic beta cell function and survival under high glucose conditions", Biochem Biophys Res Commun, 462, pp.21~26 (2015)[DOI]
- Shahen VA, "Rescue of high glucose impairment of cultured human osteoblasts using cinacalcet and parathyroid hormone", Calcif Tissue Int, 112, pp.452~462 (2023)[DOI]