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Chronic joint pain is a major health problem that can result from abnormal loading of the innervated ligamentous capsule that surrounds synovial joints. The matrix metalloproteinases-1 (MMP-1) and MMP-9 are hypothesized pain mediators from stretch-induced injuries since they increase in pathologic joint tissues and are implicated in biomechanical and nociceptive pathways that underlay painful joint injuries. There is also emerging evidence that MMP-1 and MMP-9 have mechanistic interactions with the nociceptive neuropeptide substance P. Yet, how a ligament stretch induces painful responses during sub-failure loading and whether MMP-1 or MMP-9 modulates nociception via substance P are unknown. We used a neuron–fibroblast co-culture collagen gel model of the capsular ligament to test whether a sub-failure equibiaxial stretch above the magnitude for initiating nociceptive responses in neurons also regulates MMP-1 and MMP-9. Pre-stretch treatment with the MMP inhibitor ilomastat also tested whether inhibiting MMPs attenuates the stretch-induced nociceptive responses. Because of the role of MMPs in collagen remodeling, collagen microstructural kinematics were measured in all tests. Co-culture gels were incubated for one week in either normal conditions, with five days of ilomastat treatment, or with five days of a vehicle control solution before a planar equibiaxial stretch that imposed strains at magnitudes that induce pain  in vivo  and increase nociceptive modulators  in vitro . Force, displacement, and strain were measured, and polarized light imaging captured collagen fiber kinematics during loading. At 24 h after stretch, immunolabeling quantified substance P, MMP-1, and MMP-9 protein expression. The same sub-failure equibiaxial stretch was imposed on all co-cultures, inducing a significant re-organization of collagen fibers ( p  ≤ 0.031) indicative of fiber realignment. Stretch induces a doubling of substance P expression in normal and vehicle-treated co-cultures ( p  = 0.038) that is prevented with ilomastat treatment ( p  = 0.114). Although MMP-1 and MMP-9 expression are unaffected by the stretch in all co-culture groups, ilomastat treatment abolishes the correlative relationships between MMP-1 and substance P ( p  = 0.002;  R  2  = 0.13) and between MMP-1 and MMP-9 ( p  = 0.007;  R  2  = 0.11) that are detected without an inhibitor. Collectively, these findings implicate MMPs in a painful ligamentous injury and contribute to a growing body of work linking MMPs to nociceptive-related signaling pathways and/or pain.

MMPs Regulate Neuronal Substance P After a Painful Equibiaxial Stretch in a Co-Culture Collagen Gel Model Simulating Injury of an Innervated Ligament