TRANSLATIONAL IMPACT

Abstract

Bone fractures occur in approximately 2% of the population, affecting over 6 million people annually in the USA alone. Most cases are successfully treated by reduction and surgical intervention, but delayed healing is observed in 5–10% of all fractures. Fracture repair involves numerous cell types and molecules acting at various stages of the repair process, including the inflammatory response, matrix deposition and callus remodeling. Impaired healing might thus arise from defects at any of these stages. New biological repair methods, such as growth-factor, small-molecule and stem-cell therapies, are being developed but, currently, bone morphogenetic proteins are the only growth factors used clinically. In order to make new therapies available, we need to better understand the basic cellular and molecular mechanisms of bone repair. One group of molecules with possible therapeutic potential are the matrix metalloproteinases (MMPs), an important family of enzymes that catalyze the degradation of the extracellular matrix and play a role in the normal processes of skeletal development and repair. In humans, mutations in MMP genes have been associated with skeletal diseases. In particular, the Mmp2 gene is mutated in the multicentric osteolysis with arthritis (MOA) syndrome.In this study, the authors show that Mmp2 is broadly expressed in the fracture callus at all stages of repair, and displays a distinct expression pattern compared with Mmp13 and Mmp9, which are specifically expressed in osteoblasts/chondrocytes and osteoclasts, respectively. The general MMP inhibitor GM6001 causes delayed cartilage remodeling and delayed bone formation during fracture repair, whereas Mmp2-null mutant mice only exhibit delayed bone remodeling. Impaired bone remodeling in Mmp2–/– mice is not associated with impaired osteoclast recruitment and vascular invasion of the fracture callus. The absence of Mmp2 is not compensated for by overexpression of Mmp9, Mmp13 or Mt1-Mmp (Mmp14) in the calluses of Mmp2-null mice, although there is decreased expression of the endogenous MMP inhibitor Timp2, indicating that MMP activity and callus remodeling are regulated at multiple levels.These results show that MMP2 plays a role in the remodeling phase of fracture repair and acts at later stages than MMP9 and MMP13. Members of the MMP family have distinct functions during bone repair. Some MMPs might be ideal targets to regulate inflammation and angiogenesis, whereas others, such as MMP2, might be better exploited to improve bone remodeling. However, owing to the multiple functions of MMPs in skeletal tissues, further in vivo analyses are necessary before therapeutic targeting of these molecules can be considered.