Sensory neuropeptides are required for bone and cartilage homeostasis in a murine destabilization-induced osteoarthritis model
Sensory neuropeptides are required for bone and cartilage homeostasis in a murine destabilization-induced osteoarthritis model
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DOI：
10.1016/j.bone.2019.115181
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发表时间：
2020-04-01
期刊：
影响因子：
4.1
通讯作者：
Graessel, Susanne
中科院分区：
文献类型：
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作者：
Muschter, Dominique;Fleischhauer, Lutz;Graessel, Susanne
大量研究证实感觉神经肽P物质(SP)和α-降钙素相关肽(α-CGRP)在骨关节炎(OA)疼痛行为中的作用。令人惊讶的是，它们对软骨和骨细胞的营养作用在骨关节炎病理中如何影响骨和软骨的结构变化方面却鲜有人关注。在此，我们试图阐明感觉神经肽在小鼠骨性关节炎病理生理过程中对骨和软骨结构变化的影响。12周龄雄性C57B1/6J野生型(WT)小鼠和缺乏SP(速激肽1(Tac1)-/-)或αCGRP的小鼠右膝关节内侧半月板(DMM)失稳，造成骨关节炎。根据OARSI组织病理学分级，我们观察到DMM术后4周有明显的软骨基质降解，而Tac1-/-评分在术后12周前与假手术组无明显差异。压痕型原子力显微镜(IT-AFM)在Tac1-/-Sham小鼠中发现了一种强大的表面区(SZ)软骨表型。与WT和α-CGRP-/-小鼠相反，Tac1-/-小鼠的SZ软骨在OA诱导2周后软化。术后2周，与Tac1-/-Sham组相比，Tac1-/-DMM组小鼠骨体积与总体积的比率(BV/TV)显著增加。12周后，与α-CGRP-/-和Tac1-/-小鼠相比，WT小鼠的BV/TV降低。纳米CT分析显示，骨关节炎诱导8周后，各组大鼠胫骨内侧骨化软骨厚度和内侧髁突直径均明显增加。半月板骨化在所有的骨性关节炎组中都有发生，但在没有神经肽的情况下明显更强。在两个神经肽缺陷小鼠品系中，观察到相应的非缺失神经肽的血清浓度增加。在生理条件下，两种神经肽都可以保护与年龄相关的骨结构变化，而在病理生理条件下，SP还显示出对骨结构保存的合成代谢作用。这两种神经肽缺陷小鼠都表现出一种内在的结构软骨基质表型，这可能改变了骨性关节炎软骨退变的进程。
Numerous studies identified a role for the sensory neuropeptides substance P (SP) and alpha calcitonin generelated peptide (alpha CGRP) in osteoarthritis (OA) pain behavior. Surprisingly, little attention has been paid on how their trophic effects on cartilage and bone cells might affect structural changes of bone and cartilage in OA pathology. Here, we sought to elucidate sensory neuropeptides influence on structural alterations of bone and cartilage during murine OA pathophysiology. OA was induced by destabilization of the medial meniscus (DMM) in the right knee joint of 12 weeks old male C57B1/6J wildtype (WT) mice and mice either deficient for SP (tachykinin 1 (Tac1) -/-) or alpha CGRP. By OARSI histopathological grading we observed significant cartilage matrix degradation after DMM surgery in alpha CGRP-deficient mice after 4 weeks whereas Tac1 -/- scores were not different to sham mice before 12 weeks after surgery. Indentation-type atomic force microscopy (IT-AFM) identified a strong superficial zone (SZ) cartilage phenotype in Tac1 -/- Sham mice. Opposed to WT and alpha CGRP -/- mice, SZ cartilage of Tac1 -/- mice softened 2 weeks after OA induction. In Tac1 -/- DMM mice, bone volume to total volume ratio (BV/TV) increased significantly compared to the Tac1 -/- Sham group, 2 weeks after surgery. WT mice had reduced BV/TV compared to alpha CGRP -/- and Tac1 -/- mice after 12 weeks. Increased calcified cartilage thickness and medial condyle diameter were detected in the medial tibia of all groups 8 weeks after OA induction by nanoCT analysis. Meniscal ossification occurred in all OA groups, but was significantly stronger in the absence of neuropeptides. Increased serum concentration of the respective non-deleted neuropeptide was observed in both neuropeptide-deficient mice strains.Both neuropeptides protect from age-related bone structural changes under physiological conditions and SP additionally demonstrates an anabolic effect on bone structure preservation in a pathophysiological situation. Both neuropeptide deficient mice display an intrinsic structural cartilage matrix phenotype that might alter progression of cartilage degeneration in OA.