Numerous studies identified a role for the sensory neuropeptides substance P (SP) and alpha calcitonin gene-related peptide (αCGRP) 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 C57Bl/6J wildtype (WT) mice and mice either deficient for SP (tachykinin 1 (Tac1)-/-) or αCGRP. By OARSI histopathological grading we observed significant cartilage matrix degradation after DMM surgery in αCGRP-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 αCGRP-/- 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 αCGRP-/- 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.

中文翻译：

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在小鼠不稳定诱发的骨关节炎模型中，感觉神经肽是骨骼和软骨稳态所必需的

许多研究确定了感觉神经肽物质 P (SP) 和 α 降钙素基因相关肽 (αCGRP) 在骨关节炎 (OA) 疼痛行为中的作用。令人惊讶的是，很少有人关注它们对软骨和骨细胞的营养作用如何影响 OA 病理中骨和软骨的结构变化。在这里，我们试图阐明感觉神经肽对小鼠 OA 病理生理过程中骨骼和软骨结构改变的影响。OA 是由 12 周龄雄性 C57Bl/6J 野生型 (WT) 小鼠和缺乏 SP（速激肽 1 (Tac1)-/-）或 αCGRP 的小鼠的右膝关节内侧半月板 (DMM) 不稳定引起的。通过 OARSI 组织病理学分级，我们在 αCGRP 缺陷小鼠中观察到 DMM 手术后 4 周后显着的软骨基质降解，而 Tac1-/- 评分与手术后 12 周前的假小鼠没有差异。压痕型原子力显微镜 (IT-AFM) 在 Tac1-/- Sham 小鼠中鉴定出强表面区 (SZ) 软骨表型。与 WT 和 αCGRP-/- 小鼠相反，Tac1-/- 小鼠的 SZ 软骨在 OA 诱导后 2 周软化。在 Tac1-/- DMM 小鼠中，手术后 2 周，与 Tac1-/- Sham 组相比，骨体积与总体积之比 (BV/TV) 显着增加。12 周后，与 αCGRP-/- 和 Tac1-/- 小鼠相比，WT 小鼠的 BV/TV 降低。通过nanoCT分析，在OA诱导8周后，所有组的胫骨内侧均检测到钙化软骨厚度和内侧髁直径增加。半月板骨化发生在所有 OA 组中，但在没有神经肽的情况下明显更强。在两种神经肽缺陷小鼠品系中都观察到相应非缺失神经肽的血清浓度增加。两种神经肽都可以在生理条件下防止与年龄相关的骨结构变化，而 SP 在病理生理情况下还显示出对骨结构保存的合成代谢作用。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，这可能会改变 OA 中软骨退化的进展。两种神经肽都可以在生理条件下防止与年龄相关的骨结构变化，而 SP 在病理生理情况下还显示出对骨结构保存的合成代谢作用。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，这可能会改变 OA 中软骨退化的进展。两种神经肽都可以在生理条件下防止与年龄相关的骨结构变化，而 SP 在病理生理情况下还显示出对骨结构保存的合成代谢作用。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，这可能会改变 OA 中软骨退化的进展。