Low-Dose and Short-Duration Matrix Metalloproteinase 9 Inhibition Does Not Affect Adhesion Formation during Murine Flexor Tendon Healing

Abstract

Background After flexor tendon (FT) injury and repair, adhesion formation is a substantial concern as it can result in loss of motion and functional disability. Mmp9 is a gelatinase that contributes to degradation of extracellular matrix and is expressed during FT healing. Mmp9-/- mice have accelerated remodeling of adhesions during FT healing, relative to wild type mice. The purpose of this study was to investigate whether Ro 32-3555, an Mmp9 inhibitor, can improve FT healing by limiting adhesion formation or enhancing remodeling of scar tissue during murine FT healing. Methods Flexor digitorum longus laceration and repair was performed in female C57BL/6J mice. Mice were treated with vehicle or the Mmp9 inhibitor Ro 32-3555 for 8 days. Analysis was performed for digit range of motion and gliding function, biomechanics, gene expression, and Mmp9 activity. Results An Mmp9 activity assay as well as zymography confirmed suppression of Mmp9 activity in mice treated with Ro 32-3555. There was no significant difference in tendon gliding or range of motion between vehicle and Ro 32-3555 treated mice. There was also no difference in tendon biomechanical properties between the two groups. Conclusions Local inhibition of Mmp9 gelatinolytic activity at the FT repair site is insufficient to alter adhesion formation, remodeling of adhesions, and mechanical properties of healing murine flexor tendons.

Murine Flexor Tendon Injury and Repair Surgery

“…This model has been used to assess knock-out mouse models 13,14 , and to test different pharmacological approaches to improve healing 15–18 . Histological analyses of this model, using immunohistochemistry and in situ hybridization, can provide important insights in to the localization of key genes and proteins during healing.…”

Human monocytes subjected to ischaemia/reperfusion inhibit angiogenesis and wound healing in vitro

“…Interestingly, proteome profiling arrays revealed that the release of several angiogenesis‐related proteins was altered in monocyte supernatants after I/R. Especially, MCP‐1, GM‐CSF, MIP‐1α, identified as some of the most enhanced proteins on both profiling arrays, have been described as potent effectors for remodelling and neoangiogenesis by promoting vascular endothelial growth factor‐A (VEGF‐A), endothelial progenitor cell (EPC) migration and recruitment of anti‐inflammatory macrophages (M2) at the site of ischaemic injury, where they participate in tissue recovery …”

“…Especially, MCP-1, GM-CSF, MIP-1α, identified as some of the most enhanced proteins on both profiling arrays, have been described as potent effectors for remodelling and neoangiogenesis by promoting vascular endothelial growth factor-A (VEGF-A), endothelial progenitor cell (EPC) migration and recruitment of anti-inflammatory macrophages (M2) at the site of ischaemic injury, where they participate in tissue recovery. [51][52][53] Besides the mentioned proangiogenetic mediators, also a few cytokines with antiangiogenetic potential like Activin A, Angiostatin and Pentraxin-3 was secreted into monocyte supernatants after I/R. The most upregulated antiangiogenic protein found in the culture media was Activin A, a multifunctional cytokine belonging to the TGF-β family.…”

Pharmacophore Modeling Studies on Known MMP-9 Enzyme Inhibitors to Identify the Important Common Features

“…Many small molecule inhibitors of MMP-9 which effectively treat cancer and arthritis have been studied in human. Figure 1 shows five MMP-9 inhibitors that have reached clinical trials (Batimastat, Marimastat, Prinomastat, Ro32-3555 and CG-S27023A) and another known inhibitor (NFH) which has a crystal structure, complex with the MMP-9 enzyme [7][8][9][10][11][12].…”