Impaired remodeling phase of fracture repair in the absence of matrix metalloproteinase-2.
The matrix metalloproteinase (MMP) family of extracellular proteases performs crucial roles in development and repair of the skeleton owing to their ability to remodel the extracellular matrix (ECM) and release bioactive molecules. Most MMP-null skeletal phenotypes that have been previously described are mild, thus permitting the assessment of their functions during bone repair in the adult. In humans and mice, MMP2 deficiency causes a musculoskeletal phenotype. In this study, we assessed the role of MMP2 during mouse fracture repair and compared it with the roles of MMP9 and MMP13. Mmp2 was expressed at low levels in the normal skeleton and was broadly expressed in the fracture callus. Treatment of wild-type mice with a general MMP inhibitor, GM6001, caused delayed cartilage remodeling and bone formation during fracture repair, which resembles the defect observed in Mmp9(-/-) mice. Unlike Mmp9- and Mmp13-null mutations, which affect both cartilage and bone in the callus, the Mmp2-null mutation delayed bone remodeling but not cartilage remodeling. This remodeling defect occurred without changes in either osteoclast recruitment or vascular invasion of the fracture callus compared with wild type. However, we did not detect changes in expression of Mmp9, Mmp13 or Mt1-Mmp (Mmp14) in the calluses of Mmp2-null mice compared with wild type by in situ hybridization, but we observed decreased expression of Timp2 in the calluses of Mmp2-, Mmp9- and Mmp13-null mice. In keeping with the skeletal phenotype of Mmp2-null mice, MMP2 plays a role in the remodeling of new bone within the fracture callus and impacts later stages of bone repair compared with MMP9 and MMP13. Taken together, our results indicate that MMPs play unique and distinct roles in regulating skeletal tissue deposition and remodeling during fracture repair.
Department of Orthopaedic Surgery, University of California at San Francisco, San Francisco, CA 94143, USA.
Shirley
S
Lieu
Erik
E
Hansen
Russell
R
Dedini
Danielle
D
Behonick
Zena
Z
Werb
Theodore
T
Miclau
Ralph
R
Marcucio
Céline
C
Colnot
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D016723:Bone Remodeling / Q000187:drug effects / Q000502:physiology*; D004151:Dipeptides / Q000494:pharmacology; D017102:Fracture Healing / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D053509:Matrix Metalloproteinase 13 / Q000172:deficiency / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000172:deficiency* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000378:metabolism; D051379:Mice; D010012:Osteogenesis / Q000187:drug effects; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
D015415:Biomarkers; D004151:Dipeptides; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D019716:Tissue Inhibitor of Metalloproteinase-2; D053509:Matrix Metalloproteinase 13; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9