The key role of proinflammatory cytokines, matrix proteins, RANKL/OPG and Wnt/β-catenin in bone healing of hip arthroplasty patients
The key role of proinflammatory cytokines, matrix proteins, RANKL/OPG and Wnt/β-catenin in bone healing of hip arthroplasty patients
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DOI：
10.1016/j.bone.2017.11.004
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发表时间：
2018-02-01
期刊：
影响因子：
4.1
通讯作者：
Karrholm，Johan
中科院分区：
文献类型：
--
作者：
Cassuto，Jean;Folestad，Agnetha;Karrholm，Johan
简介我们仍然不明白为什么有些植入物会失效，而大多数植入物在使用几十年后仍保持稳定。 RANKL/OPG（核因子κB配体/骨保护素的受体激活剂）和Wnt/β-连环蛋白途径的促炎细胞因子、基质蛋白和骨调节细胞因子对于正常骨修复是必需的，但它们在初次全髋关节置换术（THA）愈合中的空间和时间作用以前尚未显示。 材料和方法24名单侧固定良好的初次THA患者被研究为骨关节炎患者。在 18 年 (18 Y) 期间通过重复的血液样本、临床变量和 X 光照片进行前瞻性监测。 81 名健康捐献者分为三个年龄和性别匹配组，以及 20 名等待 THA 的骨关节炎患者，并作为 THA 患者储存血浆有效性的对照。分析血浆中的 C 反应蛋白 (CRP)、白细胞介素 (IL)-6、IL-8、IL-1β、肿瘤坏死因子 (TNF)-α、骨桥蛋白 (OPN)、富含半胱氨酸的酸性分泌蛋白 (SPARC/骨连接素)、骨钙素 (OC)、骨特异性碱性磷酸酶 (BALP)、I 型胶原蛋白 N 末端前肽 (P1NP)、RANKL、OPG、Wnt激动配体（Wnt）-1和Wnt-3a，以及Wnt拮抗剂硬化素，Dickkopf（Dkk）-1，Dkk-3，Dkk-4，分泌卷曲相关蛋白（sFRP）-1，sFRP-3和Wnt抑制因子-1（Wif-1）。结果关节置换术患者炎症介质（CRP，IL-6，OPN）显着增加术后第一天与术前值 (PR) 和健康受试者的比较，并在 6 周时恢复到基线。TNF-α 没有改变术前或健康受试者的相对水平。 SPARC 和 OC 以双相方式增加，第一阶段在手术后不久开始，持续 3 M (SPARC) 和 2 Y (OC)，而第二阶段在 1 Y (SPARC) 和 13 Y (OC) 达到峰值，并在 15 Y 时恢复到基础水平。BALP 在术后 3 M 达到峰值，在 2 Y 时恢复到基础水平，随后从 5 Y 持续增加，直到18 年。P1NP 术后立即增加，并在 6 年恢复到基础水平，随后在 10 年出现新峰值，并在 13 年恢复到基础水平。IL-8 和 IL-1β 在 THA 后 5 年达到峰值，并在 10 年恢复到基础水平。RANKL/OPG 和 Wnt/β-catenin 一直保持在术前水平，直到 THA 后 5 年，此时 OPG 水平持续增加，与此同时，硬化蛋白持续下降，开始并持续到 18 年。尽管 13 年 RANKL 大幅增加，但 OPG/RANKL 比率在 5 年至 18 年之间仍然很高。Dkk-1 和 sFRP-1 一直保持在基础水平，直到 5 年，随后在 7 年达到峰值，并在 15 年恢复到基础水平。同样，RANKL 在 13 年之后增加。 5 年，在 13 年达到峰值，并在 18 年恢复到基础水平，因此与 Wnt-1 一致。相比之下，Wnt3a、Dkk-3、Dkk-4、sFRP-3和Wif-1在随访过程中与术前或健康受试者的水平没有差异。结论参与创伤后骨愈合启动的促炎细胞因子的主峰与之前的结果一致。基质蛋白、P1NP 和 BALP 增加的主要阶段与 RANKL、OPG 和 Wnt/β-catenin 平行，直到 5 年仍保持在术前水平，在此阶段支持矿化基质的强烈形成以及较小程度的骨形成。 5 年时的二次促炎峰值可能是耦合骨重塑和新合成的触发因素，因为随后骨合成代谢标志物 BALP 以及 RANKL/OPG 和 Wnt/β-catenin 途径的介质水平升高。 OPG 水平和骨转换标志物 BALP 持续增加，从 5 岁持续到 18 岁，并且……
IntroductionWe still lack understanding of why some implants fail while most remain stable after decades of use. Proinflammatory cytokines, matrix proteins and bone regulating cytokines of the RANKL/OPG (receptor activator of nuclear factor kappa B ligand/osteoprotegerin) and Wnt/β-catenin pathways are mandatory for normal bone repair but their spatial and temporal role in the healing of primary total hip arthroplasties (THA) has not been previously shown.Materials and methodsTwenty-four osteoarthritis patients with one-sided well-fixed primary THA were prospectively monitored during 18 years (18 Y) with repeated blood samples, clinical variables and radiographs. Eighty-one healthy donors divided in three age- and gender-matched groups and twenty osteoarthritis patients awaiting THA and serving as control of the validity of stored plasma in THA patients, were included. Plasma was analyzed for C-reactive protein (CRP), interleukin (IL)-6, IL-8, IL-1β, tumor necrosis factor (TNF)-α, osteopontin (OPN), secreted protein acidic and rich in cysteine (SPARC/osteonectin), osteocalcin (OC), bone specific alkaline phosphatase (BALP), N-terminal propeptide of collagen type I (P1NP), RANKL, OPG, the Wnt agonistic ligands (Wnt)-1 and Wnt-3a, and the Wnt antagonists sclerostin, Dickkopf (Dkk)-1, Dkk-3, Dkk-4, secreted frizzled related protein (sFRP)-1, sFRP-3 and Wnt inhibitory factor-1 (Wif-1).ResultsInflammatory mediators in arthroplasty patients (CRP, IL-6, OPN) increased significantly on day one after surgery vs preoperative value (PR) and healthy subjects and returned to baseline at 6 W. TNF-α did not change relative preoperative level or healthy subjects. SPARC and OC increased in a biphasic fashion with the primary phase beginning shortly after surgery and lasting 3 M (SPARC) and 2 Y (OC) while the secondary phase peaked at 1 Y (SPARC) and 13 Y (OC), with both returning to basal level at 15 Y. BALP peaked at 3 M after surgery with a return to basal level at 2 Y followed by a continuous increase from 5 Y until 18 Y. P1NP increased immediately after surgery and returned to basal level at 6 W followed by a new peak at 10 Y returning to basal at 13 Y. IL-8 and IL-1β peaked at 5 Y post-THA and returned to basal level at 10 Y. RANKL/OPG and Wnt/β-catenin remained at preoperative levels until 5 Y post-THA when a sustained increase in OPG level, paralleled by a sustained decrease in sclerostin, started and lasted until 18 Y. Despite a strong increase by RANKL at 13 Y, the OPG/RANKL-ratio remained high between 5 Y and 18 Y. Dkk-1 and sFRP-1 remained at basal level until 5 Y followed by a peak at 7 Y and a return to basal level at 15 Y. Similarly, RANKL increased after 5 Y, peaked at 13 Y and returned to basal levels at 18 Y, thus coinciding with Wnt-1. In contrast, Wnt3a, Dkk-3, Dkk-4, sFRP-3 and Wif-1 did not differ from preoperative levels or healthy subjects during the course of the follow-up.ConclusionThe primary peak of proinflammatory cytokines involved in the initiation of bone healing after trauma is in line with previous results. The primary phase of increased matrix proteins, P1NP and BALP paralleled by RANKL, OPG and Wnt/β-catenin remaining at preoperative level until 5 Y, support a strong formation of mineralized matrix and to a lesser degree bone during this phase. The secondary proinflammatory peak at 5 Y is likely a trigger of coupled bone remodeling and neosynthesis as it is followed by increased levels of the bone anabolic turnover marker, BALP, and mediators of the RANKL/OPG and Wnt/β-catenin pathways. A continuous increase by OPG level and the bone turnover marker, BALP, lasting from 5 Y until 18 Y and …