Concerted Actions by MMPs, ADAMTS and Serine Proteases During Remodeling of the Cartilage Callus into Bone During Osseointegration of Hip Implants

Introduction: Although the number of patients undergoing total hip arthroplasty is constantly on the rise, we only have limited knowledge of the molecular mechanisms necessary for successful osseointegration of implants or the reasons why some fail. Understanding the spatiotemporal characteristics of signaling pathways involved in bone healing of implants is therefore of particular importance for our ability to identify factors causing implants to fail. The current study investigated the role of three families of proteases, i.e. MMPs (matrix metalloproteinases), ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) and serine proteases, as well as their endogenous inhibitors during osseointegration of hip implants that have endured two decades of use without clinical or radiological signs of loosening. Materials and methods: Twenty-four patients that had undergone primary THA due to one-sided osteoarthritis (OA) were monitored during 18 years (Y) with repeated measurements of plasma biomarkers, clinical variables and radiographs. All implants were clinically and radiographically well-fixed throughout the follow-up. Eightyone healthy donors divided in three gender and age-matched groups and twenty OA patients awaiting THA, served as controls. Plasma was analyzed for MMP-1, -2, -3, -8, -9, -10, -13, -14, tissue inhibitor of metalloproteinase (TIMP)-1, -2, -3, ADAMTS4, ADAMTS5, the serine proteases neutrophil elastase (NE), proteinase 3 (PR3) and their endogenous inhibitors, secretory leucocyte proteinase inhibitor (SLPI), trappin-2/elafin and serpina1 (alpha-1 antitrypsin). Cartilage turnover was monitored using two markers of cartilage synthesis, type II procollagen and PIICP (procollagen II C-terminal propeptide), and two markers of cartilage degradation, CTX-II (C-terminal telopeptide fragments of type II collagen) and split products of aggrecan (G1-IGD-G2). Results: MMP-1, MMP-9, ADAMTS4, NE and PR3 were above healthy in presurgery OA patients but returned to the level of healthy within 6 weeks (W) after surgery. MMPs and serine proteases were counter-regulated during this phase by TIMP-1, SLPI and trappin-2/elafin. Type II procollagen, PIICP and CTX-II increased to a peak 6 W after surgery with a gradual return to the level of controls within weeks. Significant increases by MMP-8, MMP-9, ADAMTS4, ADAMTS5, NE, PR3 and the protease inhibitors, TIMP-3 and serpina1, were seen 5 Y after hip arthroplasty paralleled by a sharp increase in the levels of the cartilage degradation markers, CTX-II and G1-IGD-G2. All the above mediators were normalized before 18 Y, except MMP-1 and MMP-9 that remained above healthy at 18 Y. MMP-14 increased immediately after surgery and remained elevated until 5 Y postsurgery before returning to the level of controls at 7 Y. Conclusion: Notwithstanding temporal differences, the molecular processes of bone repair in arthroplasty patients show great spatial similarities with the classical phases of fracture repair as previously shown in animal models. Cartilagenous callus, produced and remodeled early after hip arthroplasty, is replaced with bone 5 Y to7 Y after surgery by the concerted actions of MMP-8, MMP-9, ADAMTS4, ADAMTS5, NE and PR3, thus suggesting that a complex regulatory cross-talk may exist between different families of proteases during this transitional phase of cartilage degradation. Regulation and fine-tuning of cartilage remodeling by MMPs and ADAMTS is controlled by TIMP-3 whereas serine proteases are regulated by serpina1. Increased MMP-1 and MMP-9 beyond 10Y post-THA support a role during coupled bone remodeling.