title: Medial collateral ligament healing in macrophage metalloelastase (MMP-12)-deficient mice.
abstract: Medial collateral ligament (MCL) injuries heal by a wound repair scar response controlled by a complex cellular and cytokine environment. Many enzymes participate in wound repair, particularly the matrix metalloproteinases. We hypothesize macrophage metalloelastase (MME/MMP-12) deficiency results in impaired healing of MCL injury. One hundred fifty MME-deficient and 150 WT (MME+/+) mice underwent knee MCL transection with the opposite knee as a sham operated control. Mice were sacrificed at 3, 7, 28, 42, and 56 days. At each of the five time points, 15 mice were utilized for biological and 15 were utilized for biomechanical testing. Outcome measures were the presence of macrophages to represent the inflammatory phase of wound healing, collagen synthesis to assay for matrix repair, and biomechanical testing for repair strength. Immunohistochemistry demonstrated significantly fewer macrophages in cut MCLs from MME-deficient mice versus wild-type (WT) mice at 3, 7, 28, and 42 days (all p<or=0.04). In situ hybridization to Col1a1 mRNA in the MME-deficient cut MCLs at 7, 28, and 42 day time points showed a decreased level of type I pro-collagen mRNA compared to the WT cut MCLs (p<0.05). Biomechanical testing revealed cut ligaments from MME-deficient mice had significantly lower ultimate force and stiffness compared to cut ligaments from WT mice (p<0.001), with maximal differences of 40% at 7 days for ultimate force and 28 days for stiffness (p<0.05 by Tukey post hoc test). We conclude MME is important in the multifactorial cascade of knee MCL injury healing, showing significant differences in both the early inflammatory and in the matrix tissue synthesis phases.
authors.affiliation: Department of Orthopaedic Surgery, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, Missouri, USA. RWWright1@aol.com
authors.forename: Rick W
authors.initials: RW
authors.lastname: Wright
authors.forename: Tracy
authors.initials: T
authors.lastname: Allen
authors.forename: Hossam B
authors.initials: HB
authors.lastname: El-Zawawy
authors.forename: Michael D
authors.initials: MD
authors.lastname: Brodt
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Silva
authors.forename: Corey S
authors.initials: CS
authors.lastname: Gill
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Sandell
mesh_terms: D000818:Animals; D024042:Collagen Type I / Q000378:metabolism; D004195:Disease Models, Animal; D019544:Equipment Failure Analysis; D019084:Fluorescent Antibody Technique, Indirect; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D053508:Matrix Metalloproteinase 12 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D017888:Medial Collateral Ligament, Knee / Q000293:injuries* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D013264:Stifle / Q000601:surgery; D013314:Stress, Mechanical; D014945:Wound Healing
chemical_list: D024042:Collagen Type I; D053508:Matrix Metalloproteinase 12