A myofibroblast-mast cell-neuropeptide axis of fibrosis in post-traumatic joint contractures: an in vitro analysis of mechanistic components

Abstract

Previous studies have implicated a myofibroblast-mast cell-neuropeptide axis of fibrosis in pathologic joint capsules from post-traumatic contractures. The hypothesis to be tested is that joint capsule cells (JC) from human elbows with post-traumatic contractures and their interactions with mast cells (MC) and neuropeptides in the microenvironment underlie the pathogenesis of contractures. The hypothesis was tested using an in vitro collagen gel contraction model. The JC were isolated from human elbow capsules and mixed with neutralized PureCol collagen I. The gels were treated in various ways, including addition of MC (HMC-1), the neuropeptide substance P (SP), an NK1 receptor (SP receptor) antagonist RP67580 and the mast cell stabilizer ketotifen fumarate (KF). The collagen gels were released from the wells and gel size (contraction) was measured optically at multiple time points. The JC contracted collagen gels in a dose-dependent manner. This was enhanced in the presence of MC and increased further with SP. Increasing concentrations of the SP receptor antagonist, RP67580 or the mast cell stabilizer, KF decreased the magnitude of contraction. These observations identify putative mechanistic components of a myofibroblast-mast cell-neuropeptide axis of fibrosis in the joint capsules in post-traumatic contractures and potential prophylactic or therapeutic interventions.

Keywords: RP67580; contracture; ketotifen; mast cells; substance P.