Molecular basis of carpal tunnel syndrome

Abstract

Carpal tunnel syndrome (CTS) is the most common peripheral entrapment neuropathy, affecting a large proportion of the general population. CTS is characterized by paresthesia, numbness, and pain in the hands and is mainly caused by thickening and swelling of soft connective tissues that surround the median nerve. Many risk factors contribute to the development of CTS, but its underlying pathogenic mechanism is still largely unknown. Interestingly, the genetic susceptibility has been implicated in CTS. By studying two pedigrees of familial CTS, we have identified two rare heterozygous missense mutations (c.T197A, p.V66E and c.C2152T, p.R718W) in the COMP (cartilage oligomeric matrix protein) gene, which encodes a penterameric extracellular matrix (ECM) protein critical in ECM organization. We found that the oligomerization of p.V66E mutant COMP protein was impaired, and its secretion was insufficient by the tenocytes but unaffected in chondrocytes. However, the secretion of p.R718W mutant COMP was reduced by both tenocytes and chondrocytes. Clinical examinations, including magnetic resonance imaging (MRI) and electrophysiology of the median nerve, have identified macroscopic changes such as compressed median nerve, severely thickened transverse carpal ligament (TCL) and swollen digital flexor tendons, as well as slightly enlarged Achilles tendons in CTS patients. In CTS patients’ TCL, tendons, and subsynovial connective tissues (SSCT), we have observed cell death, reduced tendon/ligament stem/progenitor cells (TSPCs), and phenotypic changes such as fibrosis, angiogenesis, and adipogenesis, as well as the ultrastructural change of extracellular matrix (ECM). We have also identified a strong co-localization of the mutant COMP with the rough endoplasmic reticulum (ER), swollen/enlarged ER lumen, and activation of BIP, ATF4, CHOP, etc. genes expression, indicating an unfolded protein response mediated by prolonged ER stress in CTS patients’ tendon/ligament cells. We further generated and examined the p.V66E COMP knock-in and a COMP knock-out mouse models. The COMP knock-in mouse model, not the knock-out model, has exhibited similar molecular changes as in human patients. The phenotypes became more prominent when acute injury was introduced to the COMP knock-in mouse. The micro-damage accumulation commonly occurred and accumulated in human tendon/ligament may motivate and activate the local TSPCs. These cells normally differentiate into the mature tendon/ligament cells and repair both cellular and ECM damages. However, under the conditions of the prolonged ER stress and subsequent change of ECM niche that happened in CTS patients, they may undergo apoptosis or de-differentiate into other cell types leading to angiogenesis, adipogenesis, and fibrosis, which will eventually thicken the TCL and digital flexor tendons, and compresses the median nerve as a consequence. Furthermore, we also observed similar phenotypic and molecular changes in idiopathic and sporadic CTS patients, suggesting some of idiopathic and sporadic CTS may be caused by the similar pathogenic mechanism as we identified in familial CTS.