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

Abstract

Posttraumatic osteoarthritis (PTOA) is a well-recognized public health burden without any disease modifying treatment. This occurs despite noted advances in surgical care in the past 50 years. Mitochondrial oxidative damage pathways initiate PTOA after severe injuries like intraarticular fracture that often require surgery and contribute to PTOA after less severe injuries that may or may not require surgery like meniscal injuries. When considering the mitochondrial and redox environment of the injured joint, we hypothesized that activation of heme metabolism, previously associated with healing in many settings, would cause prototypic mitochondrial reprogramming effects in cartilage ideally suited for use at the time of injury repair. Activation of heme metabolism can be accomplished through the gasotransmitter carbon monoxide (CO), which activates hemeoxygenase-1 (HO1) and subsequent heme metabolism. In this study, we employed unique carbon monoxide (CO)-containing foam (COF) to stimulate heme metabolism and restore chondrocyte oxygen metabolism in vitro and in vivo. Doxycycline-inducible, chondrocyte-specific HO1 overexpressing transgenic mice show similar mitochondrial reprogramming after induction compared to COF. CO is retained at least 24 h after COF injection into stifle joints and induces sustained increases in heme metabolism. Lastly, intraarticular injection of COF causes key redox outcomes without any adverse safety outcomes in rabbit stifle joints ex vivo and in vivo. We propose that activation of heme metabolism is an ideal adjuvant to trauma care that replenishes chondrocyte mitochondrial metabolism and restores redox homeostasis.