2020, Vol. 39文章信息
- 买娟娟, 韩莉, 叶倩云, 李玲玉, 陈伊
- MAI Juanjuan, HAN Li, YE Qianyun, LI Lingyu, CHEN Yi
- 糖尿病性骨关节炎的研究进展
- A review of diabetes mellitus complicated with osteoarthritis
- 天津中医药大学学报, 2020, 39(3): 341-345
- Journal of Tianjin University of Traditional Chinese Medicine, 2020, 39(3): 341-345
- http://dx.doi.org/10.11656/j.issn.1673-9043.2020.03.20
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文章历史
收稿日期: 2020-01-19
2. 暨南大学附属第一医院, 广州 510632
2. The First Affiliated Hospital of Ji'nan University, Guangzhou 510632, China
糖尿病(DM)是极其常见的慢性代谢疾病, 骨关节炎(OA)则是最常见的退行性关节疾病。DM可加剧OA关节软骨代谢、软骨下骨重塑、滑膜炎症等多个病理环节并对治疗结局产生影响。笔者通过查阅近年来的相关文献, 详细汇总了DM性OA的研究概况, 以期为深入认识DM性OA奠定基础, 也为该病的防治提供更好的思路。
1 DM与OA的流行病学研究DM发病人群与日俱增, 预计到2035年全世界成年人的发病数量将达到5.92亿; 中国人群在近30年内发病率也呈现急剧上升状态, 2013年全国疾病调查表明中国成年人的DM总患病率为10.9%, DM前期患病率为35.7%, 中国已是全球最大的DM流行区域, 患病人数还将持续增加[1-2]。OA是好发于老年人的关节疾病, 据估计全球有3.5亿以上的人罹患了OA, 其中18岁以上的人口占25%, 在中国约3%的人患有OA, 65岁以上人群大于50%[3-5]。OA和DM因高发病率和共同的危险因素常共存, 1项研究表明在2010-2012年时美国已经有近半数(47.3%)的DM患者患有某种形式的关节炎[6]。
2 DM是OA的独立危险因素2型糖尿病(T2DM)是严重OA发生和发展的独立危险因素, 长期DM病程将对膝关节和髋关节呈进行性破坏, 影响关节的完整性, 这种持续的关节损伤与年龄和体质量并不相关[7]。1项临床研究表明T2DM可作为男性膝关节OA关节间隙减少的预测因子[8]。
2.1 DM加剧OA病理进展有学者统计4年内影像学核磁检查的差异, 证实了DM患者在4年内软骨和半月板损伤明显加重, DM患者软骨T2值增加较快, 软骨纹理成分均一性增加, 膝关节软骨基质退变加速[9-10]; DM能降低骨重塑, 空腹血糖浓度过高可使膝关节骨髓损伤, 而骨髓损害是预测OA结构损害的特征之一。Davies-Tuck等[11]研究提示女性空腹血糖浓度与胫骨软骨体积丢失率及骨髓病变发生率呈显著正相关; 滑膜炎与临床症状相关并且可反映OA的关节退化[12]。Schett等[13]的研究表明与非DM患者相比, DM患者膝关节滑膜炎、关节腔积液的单发和双侧征象明显增多, 而这与体重指数也无关联。
2.2 DM加剧OA手术风险与非DM合并OA患者相比, DM合并OA的患者表现出更多的残疾和更严重的疼痛[14], 可能需要更早地进行关节置换, 有研究表明DM可增加初次全膝关节置换术围手术期失血量及延缓术后功能康复[15]。DM还可以引发多种手术并发症, 最为常见的是增加术后假体感染率, 这相当于非DM患者的6.87倍[16]。Rajamaki等[17]对193例接受髋膝关节置换术后2年的患者随访发现, DM患者术后出现关节持续疼痛的比率也较高, DM与术后疼痛紧密相关。
3 DM影响OA的机制研究OA病理改变包括关节软骨退变、软骨下骨重塑、骨赘形成、滑膜炎症、韧带变性、膝关节半月板和关节囊肥大以及关节周围肌肉、神经、囊和局部脂肪垫损伤等[18-19]。DM形成的高糖环境对OA进展的各病理环节造成影响。
3.1 高糖环境促进关节软骨退变以往的研究表明正常人软骨细胞通过调节葡萄糖转运蛋白-1(GLUT-1)的合成和降解来调节细胞外葡萄糖浓度的变化, 高糖环境软骨细胞不能下调GLUT-1蛋白, 这将积累更多的葡萄糖并产生大量的活性氧(ROS), 促进软骨细胞退行性改变[20]。体外研究表明高糖水平可降低脱氢抗坏血酸向软骨细胞的转运, 影响Ⅱ型胶原的合成, 随着时间的推移, 胶原质量下降[21]。此外骨胶原网络中非酶糖基化产物即高级糖基化终产物(AGEs)浓度的增加与许多骨的力学性能有关, 包括极限强度、屈服强度和断裂韧性, DM患者骨与软骨中AGEs有较高水平的表达, 这将增加关节软骨的硬度和脆性, 机制可能是由于AGEs增加炎症以及阻碍软骨重吸收能力, 导致组织退化加速加重[22-24]。高糖也通过氧化应激和多元醇途径增强白细胞介素-1β诱导的软骨细胞炎症反应, 还可通过诱导成纤维样滑膜细胞内质网应激, 使病变滑膜分泌炎症和降解因子加剧高糖对关节软骨的损害, 降低关节软骨质量, 长距离跑步刺激下OA更加易感[25-26]。此外局部高葡萄糖浓度可导致间充质, 肌肉和脂肪来源的干细胞的软骨形成分化减少, 这可能进一步降低OA中已经减少的潜在软骨再生[27]。
3.2 高糖环境促进关节软骨下骨重塑T2DM与全身骨重建异常和骨丢失有关, 尤其是软骨下骨重塑异常, 与单纯骨关节炎相比, T2DM和OA患者的骨矿化增高且不均匀, 可能的机制包括高糖使软骨下骨弹性模量明显降低、激活破骨细胞、形成较大的骨髓腔, 这些将改变显微结构及力学损伤加剧软骨损伤[28-29]。
3.3 高糖环境加剧滑膜炎症滑膜炎症发生在OA的早期和晚期, 滑膜炎症产生细胞因子、一氧化氮、前列腺素E2和神经肽等分解和促炎介质, 打破软骨基质降解和修复的平衡, 导致软骨分解过程中蛋白水解酶的过量产生, 软骨改变反过来又加剧滑膜炎症, 造成恶性循环[30]。Hamada等[31]研究表明T2DM合并OA患者滑膜中巨噬细胞含量、肿瘤坏死因子(TNF)水平、DM相关炎症标志细胞间黏附因子-1(ICAM-1)表达明显高于非DM合并OA患者, 此外在小鼠和人类滑膜中含有丰富的胰岛素受体表达, T2DM合并肥胖OA的患者滑膜也会发生胰岛素抵抗, 这将降低胰岛素抑制炎性和分解代谢介质产生的能力, 加重OA[32]。
3.4 高糖环境改变关节内分泌物成分张鸽[33]研究认为高糖内环境是通过上调Wnt1、Wnt10b表达继而激活经典的Wnt/β-catenin信号转导通路, 促进OA大鼠膝关节液中细胞周期蛋白(Cyclin D1)、基质金属蛋白酶(MMP)-7、MMP-2和MMP-9的表达, 加重OA大鼠膝关节病理损伤。还有研究表明DM性OA患者滑膜液中MMP-1、MMP-7、MMP-8、MMP-9、MMP-10和MMP-12水平高于OA患者与正常人, 这可能是DM患者易患OA的重要原因[34]。
4 DM合并OA的治疗措施 4.1 基础研究现状Ribeiro等[35]的研究表明雷帕霉素对OA-DM小鼠的软骨损伤和滑膜炎症均有减轻作用。维生素E对单碘乙酸钠和DM诱导的大鼠膝关节软骨损伤的改善作用[36]。关节内注射脂肪源性干细胞可以通过抑制糖基化介导的炎症级联和软骨组织的再生, 保护DM环境中膝关节的完整性[37]。使用重组人甲状旁腺素可能通过恢复软骨下骨的稳态逆转1型糖尿病(T1DM)小鼠OA早期软骨下骨骨量丢失, 在T1DM OA发生早期起到保护作用[38]。口服肌肽可通过ROS/核转录因子-κB (NF-κB)途径抑制炎症对T2DM诱导的OA具有软骨保护作用[39]。联合鲑鱼降钙素(SCT)和omega-3脂肪酸(N-3)较两者单一用药更能改善DM性OA[40]。低强度脉冲电磁场可减轻T2DM小鼠松质骨微构筑的恶化和皮质骨厚度的降低, 还显著改善小鼠的生物力学全骨结构特性和组织水平的小梁骨材料特性, 小鼠骨形成明显增加, 而骨吸收无明显增加[41]。ElKarib[42]研究表明胰岛素联合游泳运动、胰岛素和钒可减轻OA疾病进展, 这可能是由于炎症和氧化应激的生物标记物被完全抑制所致。
4.2 临床研究现状1项系统性回顾研究认为治疗DM合并OA, 最常用的抗OA药物(包括扑热息痛、非甾体抗炎药物和皮质类固醇注射)的安全性问题逐渐增多, 但是口服氨基葡萄糖和关节内注射透明质酸还是安全有效的[43]。研究表明环氧化酶-2(COX-2)抑制剂联合二甲双胍治疗DM性OA患者的关节置换手术率低于未联合治疗的患者, 这可能是由于联合治疗减少了炎症因子的产生[44]。施伟丽[45]的研究表明T2DM合并OA组血清血管内皮生长因子、成纤维细胞生长因子2、结缔组织生长因子、转化生长因子-β 4种血管生成因子高表达可能共同参与了DM性OA的发生、发展, 有望通过阻断或抑制其生成预防或治疗该病。与不使用胰岛素的T2DM患者相比, 在胰岛素治疗下DM性OA患者有较少的X线骨赘形成[46]。膳食总量和谷类作物纤维与OA患者膝关节疼痛的恶化呈显著负相关, 较高的总纤维摄入量与较低的症状性OA风险有关[47]。有研究也强调定期定量适宜强度的体力运动是减轻老年OA和T2DM患者身体损害的有效干预措施[48]。在中医药疗法方面, 肖颖馥[49]研究表明采用以桂枝、附子、川乌等药物组方的温经通络外敷方热敷能明显改善T2DM合并膝骨关节炎患者疼痛及关节活动情况, 尤其是对关节沉重、关节酸楚、关节寒冷等临床症状的改善尤佳。徐菊茂等[50]使用独活、苍术、生薏苡仁等组方的中药熏喷联合硫酸氨基葡萄糖胶囊治疗18例膝骨关节炎患者, 取得较好的疗效。
总之, DM合并OA患者目前的治疗方案以对症治疗为主, 药物控制DM对OA的发病率没有影响, 但减缓了OA的进展[51]。
5 总结与展望DM合并OA的现象普遍存在, DM可加速关节软骨退变, 促进关节下骨重塑, 诱导滑膜炎症及改变关节液成分加剧OA进展。临床及基础研究证实控制血糖及调整生活方式对于DM性OA的防治尤为重要, 但目前尚未研发出特效药物, 在充分认识DM对OA病理进展、发病机制及治疗预后的多重影响外, 仍需要探讨更多的治疗方法, 中医药有望在DM性OA的防治中发挥巨大作用, 希望未来研究者能够充分发挥中医中药的优势创建更多的治疗方法, 提取更高效的中药成分控制疾病进展。
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