Matrix metalloproteinases and failed fracture healing

During fracture healing and the resulting formation of new bone, an extensive amount of extracellular matrix is synthesized which subsequently undergoes enzymatic remodeling and then mineralization. The remodeling process of mostly collagenous molecules is largely attributable to matrix metalloproteinases (MMPs). A variety of members of this protease family and its respective inhibitors – termed tissue inhibitors of matrix metalloproteinases (TIMP) – have been found to be closely related to the fracture healing process. Delays in bone healing or even nonunion could be related to the concentrations of these enzymes or their behavior over time. In this study, serum samples were prospectively collected from patients who had undergone surgical treatment for limb fracture. Serum probes from 15 patients with nonunion of fractures 4 months after surgery have been compared to 15 matched patients with normal bone healing. Postoperative time courses of serum concentrations of MMP-1/-2/-3/-8/-9/-13 as well as TIMP-1/-2 were analyzed using commercially available enzyme immunoassays. Comparison between both collectives revealed significantly elevated serum concentrations of proMMP-1 in the nonunion group at 2 and 24 weeks after surgery. Similar findings were found for MMP-8 at 2, 4 and 8 weeks. At 1 week after surgery, TIMP-1 serum concentrations were significantly lower in nonunion patients when compared to patients with normal bone repair. We have been able to show for the first time the course of serum concentrations of MMPs and TIMPs during normal and delayed fracture healing. Characteristic time courses of systemic MMP- and TIMP-levels could be a reflection of local enzyme regulatory mechanisms during fracture healing. An altered balance of the MMP/TIMP system in favor of proteolytic activity as shown in our investigation may be involved in the pathophysiological processes leading to fracture nonunion.