Remodeling of murine intrasynovial tendon adhesions following injury: MMP and neotendon gene expression

Abstract

Tendon injury frequently results in the formation of adhesions that reduce joint range of motion. To study the cellular, molecular, and biomechanical events involved in intrasynovial tendon healing and adhesion formation, we developed a murine flexor tendon healing model in which the flexor digitorum longus (FDL) tendon of C57BL/6 mice was transected and repaired using suture. This model was used to test the hypothesis that murine flexor tendons heal with differential expression of matrix metalloproteases (MMPs), resulting in the formation of scar tissue as well as the subsequent remodeling of scar and adhesions. Healing tendons were evaluated by histology, gene expression via real-time RT-PCR, and in situ hybridization, as well as biomechanical testing to assess the metatarsophalangeal (MTP) joint flexion range of motion (ROM) and the tensile failure properties. Tendons healed with a highly disorganized fibroblastic tissue response that was progressively remodeled through day 35 resulting in a more organized pattern of collagen fibers. Initial repair involved elevated levels of Mmp-9 at day 7, which is associated with catabolism of damaged collagen fibers. High levels of Col3 are consistent with scar tissue, and gradually transition to the expression of Col1. Scleraxis expression peaked at day 7, but the expression was limited to the original tendon adjacent to the injury site, and no expression was present in granulation tissue involved in the repair response. The MTP joint ROM with standardized force on the tendon was decreased on days 14 and 21 compared to day 0, indicating the presence of adhesions. Peak expressions of Mmp-2 and Mmp-14 were observed at day 21, associated with tendon remodeling. At day 28, two genes associated with neotendon formation, Smad8 and Gdf-5, were elevated and an improvement in MTP ROM occurred. Tensile strength of the tendon progressively increased, but by 63 days the repaired tendons had not reached the tensile strength of normal tendon. The murine model of primary tendon repair, described here, provides a novel mechanism to study the tendon healing process, and further enhances the understanding of this process at the molecular, cellular, and biomechanical level.

Sodium cromolyn reduces expression of CTGF, ADAMTS1, and TIMP3 and modulates post‐injury patellar tendon morphology

“…Mast cells have also been implicated in the process of scarring (fibrosis), 29 a well-known negative sequela of tendon repair. 30 Sodium cromolyn is available as a mast cell stabilizer for local or systemic application for conditions including asthma, dermatitis, mastocytosis, and rheumatoid arthritis. Although SC treatment influenced the expression of genes related to extracellular matrix metabolism in the current study, the exact mechanisms of action remain to be elucidated.…”

Genetic Variation, Protein Composition and Potential Influences on Tendon Properties in Humans

“…Further studies examined the ultrastructural, compositional and mechanical characteristics of the Achilles tendon in rodents deficient in GDF-5, and found the maximum load to failure decreased possibly due to significantly less collagen, an increase in irregularly shaped Col I fibrils and compromised material behaviour (decrease in strength and stiffness) [140][141][142]. Therefore unsurprisingly, GDF-5 has been shown to increase mechanical strength in these rodent models [143][144][145][146]. These studies are further supported at a cellular and gene level by studies showing an improved collagen organisation with GDF-5 treatment [147,148], as well as an increased expression of genes and synthesis of the components of tendon ECM, in particular, Col I, Ten C and MMP-3 [149].…”

Effect of reversed polarity microcurrent electrical stimulation on an experimentally induced Achilles tendon injury in male albino rats

“…αSMA immunostaining, × 400. of these fibrils into bundles of collagen becomes easily discernible by the 21st postoperative day. Other researchers [30] confirmed that this strictly linear uniaxial organization of collagen fibrils and the linear alignment of the spindle-shaped tenocytes between them have to be re-established in tendon during healing-remodeling processes. Accordingly, in the present study, the best healing results were found in subgroup IVb.…”