Activation of Heme Metabolism Promotes Tissue Health After Intraarticular Injury or Surgical Exposure

Abstract

AbstractThis study began with the hypothesis that combinations of traumatic injuries and the rigors of intraarticular surgical care applied to repair these injuries might cause similar damage to articular cartilage through well characterized pathways such that patients receiving intraarticular surgery may benefit from therapeutic adjuvants to surgical care in a wide variety of trauma settings. Our research group has identified critical mitochondrial oxidative damage pathways whereby posttraumatic osteoarthritis (PTOA) is initiated after intraarticular fracture, meniscal injury, and a wide variety ofin vitromodels. With increasing enthusiasm for translation of mitochondrial strategies in orthopedics, we propose that activation of heme metabolism, previously associated with healing in many settings, causes prototypic mitochondrial reprogramming effects in cartilage ideally suited to use perioperatively. In this study, we employed carbon monoxide (CO)-containing foam (COF) to stimulate heme metabolism and restore chondrocyte oxygen metabolismin vitro. Heme-oxygenase-1 (HO1), the initiating enzyme of heme metabolism, has anti-inflammatory, antioxidant, and pro-metabolic effects well characterized in other tissues. We utilized a cartilage-specific HO1 overexpressing transgenic mouse strain to demonstrate specific features of the mitochondrial reprogramming biology under examination. We then demonstrated intraarticular injection of COF and key redox and safety outcomes in rabbit stifle jointsex vivo. We propose that activation of heme metabolism is an ideal adjuvant to trauma care that replenishes mitochondrial metabolism and restores redox homeostasis after intracellular insult from trauma.