Bone metabolic modulators for osteoarthritis: curative efficacy, problems and prospects

doi:10.3969/j.issn.2095-4344.0816

Abstract

Abstract:

BACKGROUND: Osteoarthritis is a degenerative disease of the joints, mainly characterized by degeneration of articular cartilage and subchondral bone sclerosis, resulting in joint pain and decreased function in patients. In recent years, bone metabolism modulators have become a research hotspot and applied in clinic.
OBJECTIVE: To review the mechanism and curative efficacy of bone metabolic modulators for osteoarthritis.
METHODS: The first author retrieved PubMed and CNKI databases for relative articles published from January 2000 to June 2017. The keywords were “osteoporotic, bone metabolic modulators, osteoarthritis, joint, PTH, CT” in English and Chinese, respectively. The literature concerning the effects and mechanisms of bone metabolic modulators on osteoarthritis was extensively reviewed and comprehensively analyzed.
RESULTS AND CONCLUSION: Bone metabolic modulators have potential protective effects on osteoarthritic joints, preventing cartilage and subchondral bone destruction, reversing osteoarthritis-like joints change and delaying the destruction of osteoarthritic joints. The bone metabolic modulators combined with non-steroidal anti-inflammatory drugs can reduce dosages of related medicines and decrease the side effects caused by single medicine, which may have better therapeutic effects.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: Tissue Engineering, Joints, Osteoporosis

CLC Number:

R318

Kong Qing-fu1, Gou Yu2, Tian Fa-ming3, Zhang Liu4. Bone metabolic modulators for osteoarthritis: curative efficacy, problems and prospects[J]. Chinese Journal of Tissue Engineering Research, 2018, 22(24): 3907-3913.

Figures/Tables 1

2.1 骨代谢调节剂的相关研究骨关节炎发展过程中，软骨降解酶合成与分解代谢失调致使软骨基质流失明显，与此同时骨关节炎关节异常应力负荷直接作用于软骨，可加速软骨退变，以此促进骨关节炎进展[15]。大量学者通过研究后发现，软骨下骨高骨重塑加速骨代谢，骨代谢调节剂如甲状旁腺激素、选择性雌激素受体调节剂、二膦酸盐类药物、降钙素和骨化三醇等在调节骨代谢，维持骨合成、骨吸收代谢平衡和抑制软骨退变方面具有重要作用，可以改善关节炎症环境进而减慢骨关节炎进展[16]。 2.1.1 骨合成促进剂甲状旁腺激素(parathyroid hormone，PTH)是一条多肽链，由甲状旁腺分泌的[17]，此多肽链的组成为84个氨基酸，是人体重要激素之一，主要作用是维持机体的钙、磷代谢处于平衡状态，其靶器官主要包括骨骼、小肠和肾脏等[18]。目前人工合成的PTH(1-34)(特立帕肽)已经被批准为用于治疗骨质疏松症常用的药物[19]，这也是美国食品和药物管理局(food and drug administration，FDA) 惟一批准的用于促进骨形成的药物[20]。通过对临床病例的Meta分析[21]，应用PTH(1-34)治疗骨质疏松和骨关节炎的患者取得良好效果，能增加患者骨密度，降低血清骨特异性碱性磷酸酶和C端肽水平，维持骨关节炎关节健康，延缓骨关节炎的进展；同时发现PTH(1-34)和二膦酸盐类药物如阿伦膦酸钠联合使用，可以明显减少二膦酸盐类药物的不良反应，因此入选为临床治疗骨质疏松和骨关节炎的常用药物。一项包括5 880例参加了第五次国家健康和营养调查的参与者横断面研究，所有参与者根据Kellgren-Lawrence等级评估骨关节炎分级都在2级以上，用化学发光法测定其血清PTH含量。结果显示诊断为放射性膝关节骨性关节炎的临床症状较重的参与者其血清PTH含量偏高，提示与自身激素水平高低相关联。这表明骨关节炎发生后刺激内源性PTH的释放，拮抗关节周围炎症的发生发展，因此可通过补充外源性PTH达到治疗骨关节炎的目的[22]。由于PTH在骨代谢方面具有双重作用即：间歇使用PTH对于骨形成能够起到促进作用，然而连续应用PTH便会造成骨吸收，表现双重作用的具体机制尚未阐明，因此临床应用需要进一步观察研究。通过豚鼠模型研究发现，在PTH(1-34)的作用下明显增加了软骨组织中Caspase-3的表达，同时在软骨下骨方面增加了骨量和骨体积分数，这些结果表明PTH (1-34)能够抑制软骨的降解，同时也能在维持完整的软骨下骨结构的方面发挥重要作用[23]。Yan等[24]研究了PTH (1-34)对自发性骨关节炎豚鼠的作用，发现在软骨组织中基质金属蛋白酶13和骨硬化蛋白的表达均能够被PTH (1-34)所抑制，同时也观察到PTH(1-34)对软骨下骨起到保护的作用。Orth等[25]研究新西兰白兔关节炎模型发现，PTH (1-34)能够增加骨小梁的骨密度，有抑制软骨退化的作用。PTH可作用于软骨细胞的基础上对软骨下骨发挥作用，增强软骨下骨的硬度，改善软骨下骨的骨重塑，延缓骨关节炎的进展[26]。Lugo等[27]用新西兰白兔制造骨质疏松模型后，对膝关节处理引发创伤性骨关节炎，实验组给予皮下注射PTH，对照组用同样方式给予等量生理盐水，结果发现给药组滑膜增生及纤维化的情况明显低于对照组，同时发现滑膜中Ⅰ型胶原和基质金属蛋白酶13的表达与对照组相比都显著减低，这说明PTH对骨关节炎起到治疗作用。由此可见，PTH对骨关节炎患者治疗作用通过两方面来实现：第一，在软骨细胞方面可以抑制软骨细胞退化，加速其细胞基质合成，减慢软骨细胞终末期成熟分化，维持软骨正常功能；第二，在软骨下骨方面，调节钙磷代谢增强骨密度，增加骨小梁骨量和软骨下骨的骨体积分数，对抗关节软骨异常应力，保证关节软骨的完整性，发挥显著的软骨保护和减慢骨关节炎进展的效应，这些作用均可延缓骨关节炎病变达到治疗目的。 2.1.2 骨吸收抑制剂选择性雌激素受体调节剂(selective estrogen receptor modulators，SERMs)：是一类人工合成的化学结构各异且功能多样的非类固醇药物[28]，对雌激素具有激动作用。由于对骨组织产生激动作用，抑制软骨下骨重塑，保护软骨下骨的正常结构，目前雷洛昔芬等已经被FDA批准用于骨质疏松的治疗和预防[29]。直接作用于软骨下骨，对骨组织产生激动作用的同时又避免了雌激素治疗而引起的相关不良反应，所以为选择性雌激素受体调节剂应用于骨关节炎的治疗提供了前提条件[30]。选择性雌激素受体调节剂可同时作用于骨关节炎关节的关节软骨和软骨下骨，也能够直接或间接作用于关节周围的软组织比如滑膜、肌肉、韧带和其他软组织等，发挥对关节及周围组织的保护作用[30]。临床研究发现，妇女在绝经后骨关节炎的发病率显著增加，提示雌激素的减少与骨关节炎的发生发展相关联，说明雌激素可直接作用于关节组织[31]。他莫西芬作为特殊的雌激素类化合物，对骨关节炎的作用效果已经得到认可，通过防止Ⅱ型胶原的降解并且增加其合成起到治疗骨关节炎的作用[29]。其他观察研究发现，对于膝关节骨关节炎患者，雷洛昔芬能显著减轻患者疼痛，减少关节软骨下骨的损害，抑制软骨下骨的高重塑等异常改变，避免软骨下骨的损伤，以此延缓膝关节骨关节炎相关疾病进展[32]。在对骨代谢作用的研究中[33-35]，学者们发现选择性雌激素受体调节剂可以在骨转换方面发挥重要作用，维持或者增加软骨下骨的骨密度，完善软骨下骨的力学性能，还能改善软骨下骨的显微结构降低骨转换，增加骨强度避免软骨下骨结构进一步被破坏，从而减少骨质疏松性骨关节炎的发生。在兔的骨关节炎模型和体外培养人类软骨细胞实验中，发现雷洛昔芬可增加软骨细胞活性，拮抗白细胞介素1β诱导的软骨细胞发生骨关节炎，减少caspase-3的蛋白表达；抑制软骨细胞凋亡，减少软骨破坏并拮抗诱导剂对软骨的损害作用，从而延缓骨关节炎的进展[36-38]。在软骨下骨方面，苯卓昔芬可促进软骨下骨的矿化，增加软骨下骨的骨基质中无机盐的含量，加强软骨下骨骨密度以及骨强度，因此对骨关节炎关节软骨达到保护的目的[39]。在骨关节炎的发生发展过程中，左美罗昔芬能阻止骨质疏松导致的骨量减少，也能维持骨密度接近正常水平，加强软骨下骨功能和减轻骨关节炎样软骨改变延缓骨关节炎发展[40]，总之，选择性雌激素受体调节剂能减少骨关节炎的发生和发展。随着骨关节炎病程的不断进展，患者的关节炎症会逐渐加重，炎症能够促进关节损害并加速骨关节炎的发展，例如滑膜炎对骨关节炎的病理变化影响较大，特别是关节炎晚期炎症会进一步加重关节及周围损伤。在小鼠关节炎模型中，Andersson等[41]发现雷洛昔芬可减轻滑膜炎，抑制软骨破坏和减低炎症相应血清学指标，这表明雷洛昔芬具有抗炎症功能并有阻止关节组织被破坏的作用。软骨细胞在体外培养的过程中给予炎性因子白细胞介素1β，在炎性因子刺激的诱导下产生骨关节炎样病理改变，这一现象证实了炎症与骨关节炎患者的病情进展密切相关。在人类软骨细胞培养中，拉索昔芬可以阻止白细胞介素1β诱导的软骨骨关节炎样改变，炎性物质的表达明显减少，检测软骨细胞中促炎介质的浓度同样也有所下降，表明拉索昔芬在对抗炎症方面起了重要作用，既减轻关节炎症同时又改善晚期骨关节炎患者的关节功能[37，42]。5-氮杂胞苷被用于诱导体外培养的大鼠关节软骨细胞发生骨关节炎样改变，发生骨关节炎样变后用雷洛昔芬对软骨细胞进行治疗，10 d后测定caspase-3的活性、测定蛋白聚糖、Ⅱ型胶原、Ⅹ型胶原、碱性磷酸酶和基质金属蛋白酶等蛋白的表达。用三维模型对琼脂糖软骨细胞的基质沉积和力学性能进行了评价，结果表明经雷洛昔芬治疗后减少了骨关节炎相关的基因表达，抑制细胞凋亡和基质金属蛋白酶13、基质金属蛋白酶3的蛋白表达。同时与未治疗的大鼠软骨细胞相比雷洛昔芬也增加了Ⅱ型胶原蛋白和蛋白聚糖的基因表达。在三维模型评测中，雷洛昔芬治疗导致胶原沉积增加并且改进了软骨机械性能，刺激骨关节炎相关基质的活性，这些结果提供了有力证据证明应用雷洛昔芬能够阻止或减少骨关节炎的基质退化，延缓骨关节炎进展[43]。综上所述，选择性雌激素受体调节剂对关节软骨和软骨下骨起维护作用，一定程度上能拮抗骨关节炎样关节退变；同时具有部分镇痛作用，对滑膜和其他关节组织也可起保护作用，从整体上维持关节健康。二膦酸盐类药物：是一种常见的抗骨吸收药物[44-46]，目前用于防治以破骨细胞为主的包含骨质疏松症、转移性骨肿瘤、成骨不全、高钙血症等各种代谢性骨病的最常用药物之一。Hayami等[47]用阿仑膦酸钠预防早期骨关节炎大鼠的软骨下骨吸收，发现其在骨关节炎的进展中对关节软骨产生明显的保护效应。二膦酸盐能通过抑制破骨细胞或保护成骨细胞和骨细胞起到对软骨下骨的保护作用，近年来用其治疗骨关节炎患者已有相关报道，并取得了良好的效果。临床对818例绝经后妇女进行调查[48]，其中214名患者分别服用了阿伦膦酸钠、雌激素和雷洛昔芬，对膝关节的MRI、X射线、临床的症状和体征等检查指标进行评测。服用阿伦膦酸钠和雌激素的患者软骨下骨吸收减少，骨髓的水肿样变和膝关节的疼痛也明显减轻；接受阿伦膦酸钠和雷洛昔芬治疗的老年患者在膝关节的骨关节炎进程中软骨下骨的损害明显减少，这表明对病情进展起到延缓作用。Spector等[49]在另一项临床调查中，用1年时间治疗约300例轻中度骨关节炎的患者，评测他们的疼痛、关节性能和关节灵活程度，观察到二膦酸盐能极大程度的减轻患者的疼痛，明显的抑制了软骨降解标志物Ⅱ型胶原C-端肽片段(CTX-Ⅱ)的升高，降低了骨的吸收状况。因此通过这个试验说明二膦酸盐能明显的缓解骨关节炎初期患者膝关节的疼痛症状并维持其关节的正常结构。基础实验方面，Hayami等[47]研究阿伦膦酸钠对动物骨关节炎模型中的软骨和软骨下骨的影响，发现其能明显的降低血清中的软骨寡聚基质蛋白(COMP)含量，同时减少尿中CTX-Ⅰ和CTX-Ⅱ的含量，从而减轻对关节软骨的损害作用。Muehleman等[50]学者利用新西兰大白兔膝关节内注射木瓜凝乳蛋白酶造成的骨关节炎关节模型中，用药后检测兔的尿液，发现其骨和软骨胶原的代谢受抑制，代谢产物浓度有显著的下降趋势，提示唑来膦酸能明显减轻软骨的降解作用，从而延缓骨关节炎病情进展。软骨细胞凋亡在临床和实验诱导的骨关节炎模型中都有描述[51]。阿伦膦酸钠能够保护关节软骨免于退化，减少实验性诱导骨关节炎大鼠的细胞凋亡率。还有一些学者进行了一些体内外实验，同样说明二膦酸盐对软骨及软骨下骨有保护作用[52-54]。以上结果都表明，在骨关节炎的发生发展过程中应用二膦酸盐可减轻关节软骨的降解，维护关节健康的基础上改善骨关节炎。降钙素：是一种常用的抗骨再吸收剂，能够促进成骨细胞的形成刺激其活性，还能抑制破骨细胞的活性，对骨和软骨组织的合成与代谢起到重要作用，鉴于此降钙素可以作为治疗骨质疏松的常用药物[55-56]。在破骨细胞方面，降钙素可以与降钙素受体表位相结合，抑制破骨细胞的性能从而实现减少骨吸收的作用，对于软骨的保护效应也在最近几年的基础研究和临床回访中得到证实。临床研究中抽取绝经后发生骨质疏松并患有膝关节骨关节炎的老年女性患者125例[57]，全部患者均有膝痛症状并按照骨关节炎Ⅰ-Ⅲ级分类。对所有患者肌肉注射降钙素同时联合口服骨化三醇，并服用塞来昔布缓解关节的疼痛，治疗3，6，12个月后对患者治疗前后的情况进行分析：治疗后患者疼痛和功能障碍的指标随时间延长均呈逐渐下降趋势而且也减少了塞来昔布的用量。说明骨化三醇联合降钙素治疗骨关节炎能有效缓解患者的疼痛，提高患者关节功能，减少镇痛药物的用量，减轻不良反应，不仅能够治疗骨质疏松，对骨关节炎患者来说也发挥了明显的治疗作用。另一项临床研究中，收集74例全膝关节置换术患者的膝关节滑膜组织，所有患者经放射学诊断为膝骨关节炎(Kellgren/Lawrence 3至4级)，应用免疫组织化学方法对切除的滑膜组织中降钙素基因相关肽表达细胞进行鉴定[58]。从滑膜组织中分离出CD14阳性(巨噬细胞丰富的细胞部分)和CD14阴性(成纤维细胞丰富的细胞)细胞，并用降钙素和前列腺素E2刺激培养的CD14阳性和阴性细胞，探讨降钙素和前列腺素E2对降钙素基因相关肽表达的调节作用。同时对重度骨关节炎患者的滑膜组织中降钙素基因相关肽的表达水平和轻中度骨关节炎患者的疼痛进行比较。结果表明经降钙素和前列腺素E2处理后，滑膜内层细胞降钙素基因相关肽表达减少，患者疼痛相对减轻，证明降钙素治疗骨关节炎达到明显效果。基础研究发现，降钙素能够抑制骨吸收是通过受体与配体相结合减低破骨细胞功能来实现的，皮下注射的给药方式注射降钙素可抑制骨关节炎大鼠软骨下骨中破骨细胞的功能，减少早期引起的骨形成，减少关节软骨中蛋白多糖和Ⅱ型胶原的丢失。在抑制软骨下骨早期被吸收的情况下，通过应用降钙素还减少了骨代谢平衡过程中引发的骨形成作用，这样保护了软骨下骨的完整性，减轻关节软骨的磨损，维持了关节软骨和软骨下骨整体结构的健康状态，同时还可直接作用于软骨细胞，从而延缓骨关节炎的病理进程[59-60]。降钙素能促进正常骨组织分泌足量的蛋白多糖，对创伤后骨关节炎大鼠关节软骨表现出较好的保护作用。有学者使用降钙素试验性治疗骨关节炎大鼠，认为降钙素能够阻止骨关节炎早期软骨下骨的吸收，并最终延缓软骨下骨硬化。降钙素与受体结合作用于关节软骨细胞上，结果表明降钙素促进胶原蛋白的表达使其含量增加，因此发挥保护软骨的作用[61]。在控制炎症方面，降钙素可减少细胞炎性递质白细胞介素1β的分泌，抑制软骨基质金属蛋白酶的合成与分泌，减少关节周围炎症反应，减轻因软骨细胞凋亡和关节软骨退行性改变过程引发的疼痛症状，达到对骨关节炎的治疗作用。综合以上观点能够得出结论，膝关节骨关节炎疼痛的原因与关节内不同结构释放或产生疼痛介质有关，而降钙素的生理作用在于对软骨细胞的保护作用，刺激蛋白多糖和胶原蛋白的分泌，加强降钙素对关节软骨的修复功能，维持骨组织代谢的平衡状态，减少患者关节周围炎症引起的疼痛，还能够通过抑制软骨下骨骨重塑过程减轻关节的损伤，进一步抑制软骨的磨损阻止骨关节炎继续恶化。 2.2 其他药物骨化三醇是维生素D的活性代谢产物，最早应用于骨质疏松治疗领域，近年来也用于治疗骨关节炎。其作用过程分为直接促进骨形成并增加骨量和间接抑制骨吸收，缓解临床症状、加强肌肉力量，改善神经肌肉协调性，同时起到抑制成骨细胞凋亡的作用[62]。对于体外培养的成骨细胞，骨化三醇可以加速其产生骨钙素和碱性磷酸酶，从而促进成骨细胞成熟，加强其功能活性[63]。在骨关节炎早期使用骨化三醇，能够抑制软骨下骨吸收，使与骨吸收相耦联的继发性骨质增生和硬化速度均减缓，间接保护了关节软骨。骨化三醇还能通过作用于骨关节炎软骨及软骨下骨的相关代谢因素同时调节多种细胞因子、生长因子的信号转导途径来减慢骨关节炎的进展[64-65]。在骨关节炎动物模型中发现，骨化三醇治疗组比单独模型组关节软骨基质金属蛋白酶13的表达低，表明骨化三醇抑制了基质金属蛋白酶13的表达，从而减少了Ⅱ型胶原的降解，而体外实验表明，骨化三醇能降低骨关节炎软骨细胞合成前列腺素和基质金属蛋白酶的能力，防止它们对关节软骨造成损伤，延缓骨关节病变[66]。研究提示，联合应用选择性雌激素受体调节剂和骨化三醇的治疗效果优于单独使用骨化三醇，为骨关节炎的治疗提供新方案。"

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