关键词：
Collagenase
Joints
Ligaments
Nociception
Pain
Matrix metalloproteinase
Afferent signaling
Innervated capsular tissue
Fibroblasts
摘要：
Chronic joint pain is a major healthcare challenge with a staggering socioeconomic burden. Pain from synovial joints is mediated by the innervated joint tissues. Due to its innervation, the collagenous capsular ligament that surrounds the joint encodes nociceptive signals and transmits them for pain perception. Although increases in the matrix metalloproteinases (MMPs) occur in painful synovial joints either from injury or degenerative disorders, whether and how MMPs may be mechanistically involved in joint pain is unknown. Since the interstitial collagenase MMP-1 has many roles in collagen degradation and signal transduction pathways, it may play a role in nociception from the joint capsular ligament, but this has not been evaluated. The studies in this thesis define the biomechanical and biochemical roles of MMP-1 in afferent signaling using complementary approaches in human, rat, and cell culture models to define fibroblast-neuron and collagen-neuron interactions in nociception, with and without tissue loading. MMPs in the innervated capsular tissue from patients with painful temporomandibular joint disorders are characterized and establish a role for both MMP-1, and the gelatinase MMP-9, as positive correlates with pain symptoms. Studies in the rat show that excess intra-articular MMP-1 is sufficient to induce behavioral sensitivity which is paralleled by neuronal dysregulation in both the peripheral and central nervous systems. Moreover, nociception may be initiated by the microscale catabolism of collagen molecules in the capsular ligament and its subsequent effects on the multiscale biomechanical function of ligament tissues in the presence of MMP-1. To better understand those MMP-1-induced pain mechanisms, a novel co-culture model was designed to mimic the multicellular microenvironment of the capsular ligament incorporating both fibroblasts and peripheral neurons. Biomechanical loading and biochemical degradation each increase both MMP-1 expression and that
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