University Hospital Ghent, De Pintelaan 185, 9000 Ghent, Belgium.
The Leeds Institute of Rheumatic and Musculoskeletal Medicine, 2nd Floor, Chapel Allerton Hospital, Chapeltown Road, Leeds LS7 4SA, UK.
Best Pract Res Clin Rheumatol. 2014 Oct;28(5):703-10. doi: 10.1016/j.berh.2014.10.009. Epub 2014 Nov 22.
Given that entheses are sites of high mechanical stress that concentrate the forces of large contracting muscles down onto a small footprint of bone contact, it was recognized nearly 60 decades ago that stress and injury at such sites may play a role in the pathogenesis of mechanically related enthesopathy. In recent years, the role of mechanical stress and its related consequences on inflammatory enthesitis have also been recognized. Clinical imaging studies and experimental animal models of spondyloarthropathy including tumor necrosis factor (TNF) transgenic models and interleukin (IL)-23 overexpression systems are associated with a primary enthesitis with disease subsequently spreading to adjacent joint structures including the synovium and bone. Joint mechanical stress, without discernible microdamage or injury, leads to spondyloarthritis (SpA) in a TNF transgenic model. Normal-aged human entheses often demonstrate microdamage, but it is unclear whether an abnormal response to mechanical stress alone or the need for stress-induced microdamage is involved in human disease initiation. Clinically, the contribution of mechanical stress to SpA including psoriatic arthritis (PsA) helps conceptualize the disease in a new way and provides obvious mechanistic links to skin and nail Koebner responses. It also offers novel epidemiological explanations for why PsA develops in subjects with high body mass indices most typically in the fourth and fifth decades. Molecularly, the monogenic forms of SpA including caspase recruitment domain-containing protein 14 (CARD14) and IL36RN mutations have site-specific expression of mutated proteins in the skin, thus offering a direct molecular link between local inflammation-related pathway dysregulation and local stress or injury in disease causation. Given that many of the pathways that govern both immunity and mechanical stress including extracellular-signal-regulated kinase (ERK) and mitogen-activated protein kinase (MAPK) are shared, it may be difficult to develop strategies that selectively target mechanical stress-related pathways. However, occupational- and obesity-related factors may be potentially modifiable in susceptible individuals to prevent or ameliorate disease.
鉴于附着点是机械应力高的部位，这些部位将大收缩肌的力集中在骨骼接触的小面积上，因此，近 60 年前就认识到，这些部位的应力和损伤可能在机械相关附着病的发病机制中起作用。近年来，机械应力及其相关后果对炎症性附着病的作用也得到了认识。脊柱关节炎（SpA）的临床影像学研究和实验动物模型，包括肿瘤坏死因子（TNF）转基因模型和白细胞介素（IL）-23 过表达系统，与原发性附着病有关，随后疾病扩散到相邻的关节结构，包括滑膜和骨骼。在 TNF 转基因模型中，没有明显的微损伤或损伤的关节机械应力导致 SpA。正常年龄的人附着点经常表现出微损伤，但尚不清楚是对机械应力的异常反应还是对机械应力诱导的微损伤的需求参与了人类疾病的发生。临床上，机械应力对 SpA（包括银屑病关节炎（PsA））的贡献有助于以新的方式理解疾病，并为皮肤和指甲科伯纳反应提供明显的机制联系。它还为为什么 PsA 会在大多数情况下在第四和第五个十年中身体质量指数较高的患者中发展提供了新的流行病学解释。在分子水平上，SpA 的单基因形式，包括半胱氨酸蛋白酶募集域蛋白 14（CARD14）和 IL36RN 突变，在皮肤中具有突变蛋白的特异性表达，从而在局部炎症相关途径失调和疾病发病中的局部应激或损伤之间提供了直接的分子联系。鉴于调节免疫和机械应激的许多途径，包括细胞外信号调节激酶（ERK）和丝裂原活化蛋白激酶（MAPK），都具有共享性，因此，开发选择性针对机械应激相关途径的策略可能具有挑战性。然而，职业和肥胖相关因素可能在易感个体中具有潜在的可调节性，以预防或改善疾病。
