Does Pain at an Earlier Stage of Chondropathy Protect Female Mice Against Structural Progression After Surgically Induced Osteoarthritis?
Does Pain at an Earlier Stage of Chondropathy Protect Female Mice Against Structural Progression After Surgically Induced Osteoarthritis?
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DOI：
10.1002/art.41421
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发表时间：
2020-11-04
影响因子：
13.3
通讯作者：
Vincent, Tonia L.
中科院分区：
文献类型：
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作者：
von Loga, Isabell S.;Batchelor, Vicky;Vincent, Tonia L.
目的雌性C57BL/6小鼠软骨病变较雄性小鼠轻。方法采用内侧半月板失稳(DMM)或部分半月板切除(PMX)诱导C57BL/6或DBA/1小鼠骨性关节炎模型，每组6-15只。部分小鼠去卵巢(OVX)(n=30)。对DMM后局部软骨缺损或关节固定(坐骨神经切除)后的体内修复进行评估。采用组织学分析、全膝关节基因表达分析、动物行为实验注册分析系统(LABORAS)和Linton无能试验(n=7-10)进行行为学分析。结果两种品系和两种手术后，雌性小鼠的软骨病变程度均有所减轻(减少20~75%)。PMX后雄性和雌性小鼠的活动水平相似。手术后雌性小鼠关节中一些修复相关基因增加，但体内修复差异不明显。尽管软骨病变减少，但雌性小鼠与雄性小鼠同时出现类似疼痛的行为。在建立疼痛行为时(PMX后10周)，疼痛相关基因在雌性小鼠中显著上调，包括GDNF2.54+/-0.30，Nrtn(6.71+/-1.24)，Ntf3(1.92+/-0.27)和Ntf5(2.89+/-0.48)(P<；0.01，P<；0.01，P<；0.05和P<；0.001，分别与雄性小鼠相比)。在疼痛的关节中，炎症基因在不同性别的小鼠中都没有被调节。结论我们证实雌性小鼠的结构性关节保护作用不是由于活动或内在修复差异所致。雌性小鼠与雄性小鼠在同一时间出现疼痛，但会产生一套不同的神经营养因子。我们推测，雌性小鼠对疼痛的高度敏感通过防止过度使用来保护关节。
Objective Female C57BL/6 mice exhibit less severe chondropathy than male mice. This study was undertaken to test the robustness of this observation and explore underlying mechanisms.Methods Osteoarthritis was induced in male and female C57BL/6 or DBA/1 mice (n = 6-15 per group) by destabilization of the medial meniscus (DMM) or partial meniscectomy (PMX). Some mice were ovariectomized (OVX) (n = 30). In vivo repair after focal cartilage defect or joint immobilization (sciatic neurectomy) following DMM was assessed. Histologic analysis, evaluation of gene expression in whole knees, and behavioral analysis using Laboratory Animal Behavior Observation Registration and Analysis System (LABORAS) and Linton incapacitance testing (n = 7-10 mice per group) were performed.Results Female mice displayed less severe chondropathy (20-75% reduction) across both strains and after both surgeries. Activity levels after PMX were similar for male and female mice. Some repair-associated genes were increased in female mouse joints after surgery, but no repair differences were evident in vivo. Despite reduced chondropathy, female mice developed pain-like behavior at the same time as male mice. At the time of established pain-like behavior (10 weeks after PMX), pain-associated genes were significantly up-regulated in female mice, including Gdnf (mean +/- SEM fold change 2.54 +/- 0.30), Nrtn (6.71 +/- 1.24), Ntf3 (1.92 +/- 0.27), and Ntf5 (2.89 +/- 0.48) (P < 0.01, P < 0.01, P < 0.05, and P < 0.001, respectively, versus male mice). Inflammatory genes were not regulated in painful joints in mice of either sex.Conclusion We confirm strong structural joint protection in female mice that is not due to activity or intrinsic repair differences. Female mice develop pain at the same time as males, but induce a distinct set of neurotrophins. We speculate that heightened pain sensitivity in female mice protects the joint by preventing overuse.