Joint capsule mast cells and neuropeptides are increased within four weeks of injury and remain elevated in chronic stages of posttraumatic contractures

Loss of joint motion, or joint contracture, is a common complication following injuries.1 The joint capsule is a key contributor to the formation of contractures and surgical releases to improve joint motion invariably include its removal.2 Although the anatomic importance of the joint capsule in the pathogenesis of joint contractures has been known for many years, only recently has there been description of the cellular changes associated with posttraumatic contractures.3–5 It was determined that the myofibroblast, a specialized fibro-blast expressing the contractile smooth muscle protein α-smooth muscle actin (α-SMA) and associated with contracture and fibrosis in many organ systems, is increased in numbers in joint capsules from posttraumatic contractures when compared to similar tissues from normal joints.4–6 This is true for the chronic stages of posttraumatic contractures in human elbow joints and a rabbit knee model of posttraumatic contractures.3–5 Myofibroblast numbers are increased very early in the contracture process, as early as 4 weeks after injury, in this rabbit knee model.7 The question remains as to what is contributing to this early and sustained increase in myofibroblast numbers. One possibility contributing to the early and sustained increase in myofibroblast numbers is a mast cell–neuropeptide fibrosis axis as described in skin wound healing.8 Mast cells are widely distributed throughout connective tissues, including skin and joint capsules.8–14 Mast cell granules contain preformed mediators associated with fibrosis including platelet-derived growth factor-A, basic fibroblast growth factor and endothelin-1, while the profibrotic TGF-β1 is formed upon mast cell stimulation.9,12 It is generally believed that mast cells induce a fibrotic response via involvement of connective tissue fibroblasts and myofibroblasts.9,12,15,16 It has been well described that the neuropeptides Substance P and CGRP can cause mast cell degranulation.8,11,13,14,17,18 Peptidergic nerve terminalshavebeen detectedin close association with mast cells in skin, ligament, joint capsule, and the gut.10,11,13,14,19 It was recently reported that both the density of Substance P positive fibers and the number of mast cells were increased in the pathologic palmar fascia of patients with Dupuytren’s contracture when compared to nonpathologic palmar fascia of control individuals.19 Thus, the myofibroblast–mast cell–neuropeptide pathway may represent what is abnormal (myofibroblasts), how this abnormality comes about (mast cell degranulation liberating growth factors), and why this may occur (neuropeptide induced degranulation of mast cells). As a first step to evaluate the potential involvement of this pathway in joint contracture development, the hypothesis that joint capsule mast cell and neuropeptide containing nerve fiber numbers are increased in posttraumatic contractures is tested. The objective is to evaluate this hypothesis in the acute and chronic stages of the rabbit knee model of posttraumatic contractures, as well as the chronic stages of human posttraumatic elbow contractures.