In nondiabetic C57BL/6J mice, canagliflozin affects the skeleton in a sex- and age-dependent manner.

IF 3.4 Q2 ENDOCRINOLOGY & METABOLISM JBMR Plus Pub Date : 2024-10-10 eCollection Date: 2024-12-01 DOI:10.1093/jbmrpl/ziae128
Carolyn Chlebek, Casey McAndrews, Samantha N Costa, Victoria E DeMambro, Shoshana Yakar, Clifford J Rosen
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Abstract

Canagliflozin (CANA) is a sodium glucose cotransporter-2 inhibitor that reduces blood glucose levels. Sodium glucose cotransporter-2 is primarily expressed in the kidney, but not in any bone cells, therefore effects on the skeleton are likely to be non-cell autonomous. Originally developed to treat type II diabetes, CANA use has expanded to treat cardiovascular and renovascular disease. Clinical trials examining CANA in diabetic patients have produced contradictory reports on fracture risk, but there are limited data of CANA in nondiabetic conditions. In nondiabetic preclinical models, short-term treatment with CANA negatively affected trabecular bone whereas long-term treatment reduced cortical bone mineralization in male but not female mice. To investigate the skeletal effects of an intermediate period of CANA treatment, we treated male and female C57BL/6 J mice with CANA (180 ppm) for 6 months. Age at treatment initiation was also evaluated, with cohorts starting CANA prior to skeletal maturity (3-months-old) or in adulthood (6-months-old). Longitudinal assessments of bone mineral density revealed early benefits of CANA treatment in female mice. At euthanasia, both trabecular and cortical bone morphology were improved by CANA treatment in males and females. Bone formation was reduced at the endosteal surface. CANA decreased osteoblast number in male mice and bone marrow adiposity in females. Overall, more skeletal benefits were recorded in CANA-treated females than males. Urinary calcium output increased with CANA treatment, but parathyroid hormone was not changed. Despite reduced fasting blood glucose, body composition and whole-body metabolism were minimally changed by CANA treatment. For all outcome measures, limited differences were recorded based on age at treatment initiation. This study demonstrated that in nondiabetic C57BL/6 J mice, an intermediate period of CANA treatment improved bone morphology, but reduced osteoblast and bone marrow adipocyte number as well as serum procollagen type 1 N-terminal pro-peptide in a sex-specific manner.

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在非糖尿病 C57BL/6J 小鼠中,卡格列净对骨骼的影响与性别和年龄有关。
卡格列净(CANA)是一种葡萄糖钠共转运体-2抑制剂,可降低血糖水平。葡萄糖钠共转运体-2主要在肾脏中表达,但不在任何骨细胞中表达,因此对骨骼的影响可能是非细胞自主的。CANA 最初用于治疗 II 型糖尿病,现在已扩展到治疗心血管和新血管疾病。对糖尿病患者使用 CANA 的临床试验得出了关于骨折风险的相互矛盾的报告,但 CANA 用于非糖尿病患者的数据却很有限。在非糖尿病临床前模型中,CANA 的短期治疗会对小梁骨骼产生负面影响,而长期治疗则会降低雄性小鼠的皮质骨矿化,但不会降低雌性小鼠的皮质骨矿化。为了研究 CANA 中期治疗对骨骼的影响,我们用 CANA(百万分之 180)对雄性和雌性 C57BL/6 J 小鼠进行了为期 6 个月的治疗。我们还评估了开始治疗时的年龄,各组小鼠在骨骼成熟前(3 个月大)或成年后(6 个月大)开始接受 CANA 治疗。对骨矿物质密度的纵向评估显示,CANA治疗对雌性小鼠有早期益处。安乐死时,雄性和雌性小鼠的骨小梁和皮质骨形态都通过 CANA 治疗得到了改善。骨内膜表面的骨形成减少。CANA 减少了雄性小鼠的成骨细胞数量和雌性小鼠的骨髓脂肪含量。总体而言,经 CANA 处理的雌性小鼠比雄性小鼠对骨骼的益处更大。CANA治疗后尿钙排出量增加,但甲状旁腺激素没有变化。尽管空腹血糖有所降低,但身体成分和全身新陈代谢在CANA治疗后的变化很小。在所有结果测量中,根据开始治疗时的年龄记录到的差异有限。这项研究表明,在非糖尿病 C57BL/6 J 小鼠中,CANA 中期治疗可改善骨形态,但会以性别特异性的方式减少成骨细胞和骨髓脂肪细胞数量以及血清 1 型胶原蛋白 N 端前肽。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
JBMR Plus
JBMR Plus Medicine-Orthopedics and Sports Medicine
CiteScore
5.80
自引率
2.60%
发文量
103
审稿时长
8 weeks
期刊最新文献
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