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

Abstract

The purpose of this article was to determine mast cell and neuropeptide nerve fiber numbers in joint capsules in posttraumatic contractures, as elevated numbers have been implicated in other fibrotic and contracture conditions. Twelve skeletally mature rabbits had intraarticular cortical windows removed from the medial and lateral femoral condyles and the knee joint immobilized. The contralateral unoperated limb served as a control. Equal numbers of rabbits were sacrificed 4 weeks after surgery or 40 weeks after the first surgery that included 32 weeks of remobilization. Six patients with chronic posttraumatic elbow joint contractures and six age-matched organ donor controls free of elbow contractures were also studied. Joint capsule myofibroblast, mast cell, and neuropeptide containing nerve fiber numbers were assessed with immunohistochemistry. The numbers of myofibroblasts, mast cells, and neuropeptide containing nerve fibers expressed as a percentage of total cells were significantly greater in the contracture capsules when compared to the control capsules at all time points (p < 0.0001). The range of percentages for the three components in the contracture capsules versus the controls were 41-48% versus 9-10%, 44-50% versus 11-13%, and 45-50% versus 10-12% for the acute and chronic stages of the rabbit model and the chronic stages in the human elbows, respectively. These data support the hypothesis that a myofibroblast-mast cell-neuropeptide fibrosis axis may underlie some of the pathologic changes in the joint capsule in posttraumatic contractures. Approaches designed to manipulate this axis, such as preventing degranulation of mast cells, warrant further investigation. Keywordscontracture; joint capsule; myofibroblasts; mast cells; neuropeptides 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][4][5] It was determined that the myofibroblast, a specialized fibro- CIHR Author ManuscriptCIHR Author Manuscript CIHR Author Manuscript 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][5][6] This is true for the chronic stages of posttraumatic contractures in human elbow joints and a rabbit knee model of posttraumatic contractures. [3][4][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...

Neuropeptide, Mast Cell, and Myofibroblast Expression After Rabbit Deep Flexor Tendon Repair

“…Myofibroblasts and mast cells, as well as neuropeptide-containing nerve fibers, that under normal conditions in uninjured tissues constitute Ͻ10% of the total cell population, reached levels ranging from 33% to 50% after tendon injury and subsequent repair. These levels are comparable with those described for changes in joint capsules after injury and immobilization in a rabbit knee model 6,22 as well as in specimens from patients with elbow contractures. 23 Their increase also corresponds well with the proliferative phase of healing, when tendon apoptosis is inhibited and cellularity increases.…”

The mast cell stabilizer ketotifen reduces joint capsule fibrosis in a rabbit model of post-traumatic joint contractures

“…Mast cell hyperplasia has more recently been observed within affected joint capsules GTG TGA GGA AGA GGA CAG CA TAC GTC CAG AGG CAT AGA GG 20 446 55 32 Col I GAT GCG TTC CAG TTC GAG TA GGT CTT CCG GTG GTC TTG TA 20 312 55 22 Col III TTA TAA ACC AAC CTC TTC CT TAT TAT AGC ACC ATT GAG AC 20 255 55 28 TGF-b1 CGG CAG CTG TAC ATT GAC TT AGC GCA CGA TCA TGT TGG AC 20 271 60 32 GAPDH TCA CCA TCT TCC AGG AGC AG CAC AAT GCC GAA GTG GTC GT 20 293 55 harvested from post-traumatic contractures of the human elbow and the rabbit knee [30]. Despite evidence linking mast cell activation to fibroproliferative disorders, very few studies have assessed mast cell modulation with ketotifen in animal models of fibrosis.…”

“…A variety of cell types have been shown to produce TGF-b1, including platelets, macrophages, neutrophils, activated fibroblasts and mast cells [31,32]. Compared to unaffected joint capsule specimens, which are sparsely populated by fibroblasts, numerous studies from our research group have proven the fibrotic post-traumatic joint capsule to be quite hypercellular, with mast cells and myofibroblasts representing roughly 90% of the total cell population [18,30]. Mast cells are a known source of TGFb1 and given the high densities of this cell type in contracted joint capsules it seems quite plausible that elevated TGF-b1 gene and protein expression may be a product of increased mast cell activation.…”

Intra-articular implantation of collagen scaffold carriers is safe in both native and arthrofibrotic rabbit knee joints

“…13,14 Other studies have suggested the possible influence of mast cells on the development of arthrofibrosis in the four weeks after injury. 11 The early onset of changes, both on the cellular and molecular level, seems to indicate the need for early intervention to prevent or abort the development of arthrofibrosis. Using these animal models, attempts to find an effective anti-fibrosis medication are underway.…”