McNulty Amy L, Leddy Holly A, Liedtke Wolfgang, Guilak Farshid
Department of Orthopaedic Surgery, Duke University Medical Center, DUMC 3093, Durham, NC, 27710, USA.
Naunyn Schmiedebergs Arch Pharmacol. 2015 Apr;388(4):437-50. doi: 10.1007/s00210-014-1078-x. Epub 2014 Dec 18.
Biomechanical factors play a critical role in regulating the physiology as well as the pathology of multiple joint tissues and have been implicated in the pathogenesis of osteoarthritis. Therefore, the mechanisms by which cells sense and respond to mechanical signals may provide novel targets for the development of disease-modifying osteoarthritis drugs (DMOADs). Transient receptor potential vanilloid 4 (TRPV4) is a Ca(2+)-permeable cation channel that serves as a sensor of mechanical or osmotic signals in several musculoskeletal tissues, including cartilage, bone, and synovium. The importance of TRPV4 in joint homeostasis is apparent in patients harboring TRPV4 mutations, which result in the development of a spectrum of skeletal dysplasias and arthropathies. In addition, the genetic knockout of Trpv4 results in the development of osteoarthritis and decreased osteoclast function. In engineered cartilage replacements, chemical activation of TRPV4 can reproduce many of the anabolic effects of mechanical loading to accelerate tissue growth and regeneration. Overall, TRPV4 plays a key role in transducing mechanical, pain, and inflammatory signals within joint tissues and thus is an attractive therapeutic target to modulate the effects of joint diseases. In pathological conditions in the joint, when the delicate balance of TRPV4 activity is altered, a variety of different tools could be utilized to directly or indirectly target TRPV4 activity.
生物力学因素在调节多种关节组织的生理及病理过程中发挥着关键作用，并与骨关节炎的发病机制有关。因此，细胞感知和响应机械信号的机制可能为开发改善病情的骨关节炎药物（DMOADs）提供新的靶点。瞬时受体电位香草酸亚型4（TRPV4）是一种Ca(2+)通透性阳离子通道，在包括软骨、骨和滑膜在内的多种肌肉骨骼组织中作为机械或渗透信号的感受器。TRPV4在关节稳态中的重要性在携带TRPV4突变的患者中显而易见，这些突变导致一系列骨骼发育异常和关节病的发生。此外，Trpv4基因敲除会导致骨关节炎的发展和破骨细胞功能下降。在工程化软骨替代物中，TRPV4的化学激活可以重现机械加载的许多合成代谢效应，以加速组织生长和再生。总体而言，TRPV4在关节组织内转导机械、疼痛和炎症信号方面起关键作用，因此是调节关节疾病效应的一个有吸引力的治疗靶点。在关节的病理状态下，当TRPV4活性的微妙平衡被改变时，可以利用各种不同的工具直接或间接靶向TRPV4活性。
