Browsing by Subject "Subchondral bone"

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    Inflammatory mechanisms in post-traumatic osteoarthritis: a role for CaMKK2
    (Wolters Kluwer, 2023-10-16) Riggs, Keegan C.; Sankar, Uma; Anatomy, Cell Biology and Physiology, School of Medicine
    Post-traumatic osteoarthritis (PTOA) is a multifactorial disease of the cartilage, synovium, and subchondral bone resulting from direct joint trauma and altered joint mechanics after traumatic injury. There are no current disease-modifying therapies for PTOA, and early surgical interventions focused on stabilizing the joint do not halt disease progression. Chronic pain and functional disability negatively affect the quality of life and take an economic toll on affected patients. While multiple mechanisms are at play in disease progression, joint inflammation is a key contributor. Impact-induced mitochondrial dysfunction and cell death or altered joint mechanics after trauma culminate in inflammatory cytokine release from synoviocytes and chondrocytes, cartilage catabolism, suppression of cartilage anabolism, synovitis, and subchondral bone disease, highlighting the complexity of the disease. Current understanding of the cellular and molecular mechanisms underlying the disease pathology has allowed for the investigation of a variety of therapeutic strategies that target unique apoptotic and/or inflammatory processes in the joint. This review provides a concise overview of the inflammatory and apoptotic mechanisms underlying PTOA pathogenesis and identifies potential therapeutic targets to mitigate disease progression. We highlight Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2), a serine/threonine protein kinase that was recently identified to play a role in murine and human osteoarthritis pathogenesis by coordinating chondrocyte inflammatory responses and apoptosis. Given its additional effects in regulating macrophage inflammatory signaling and bone remodeling, CaMKK2 emerges as a promising disease-modifying therapeutic target against PTOA.
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    Post-traumatic osteoarthritis: A review of pathogenic mechanisms and novel targets for mitigation
    (Elsevier, 2023-01-30) Dilley, Julian E.; Bello, Margaret Anne; Roman, Natoli; McKinley, Todd; Sankar, Uma; Orthopaedic Surgery, School of Medicine
    Post-traumatic osteoarthritis (PTOA) develops secondary to a joint injury and accounts for 12 % of all osteoarthritis. These injuries, often of the lower extremity joints, occur due to trauma or accidents related to athletic or military activities. They primarily affect younger individuals although PTOA can occur across the spectrum of age. Pain and functional disability caused by PTOA confer a heavy economic toll on patients, in addition to detrimentally affecting their quality of life. Both high energy injuries that cause articular surface fracture with or without subchondral bone disruption and low-energy injuries involving joint dislocations or ligamentous injury cause PTOA, albeit through different mechanisms. Regardless, chondrocyte death, mitochondrial dysfunction, reactive oxygen species production, subchondral bone remodeling, inflammation and cytokine release in the cartilage and synovium play integral roles in the pathogenesis of PTOA. Evolving surgical methods are focused on stabilizing articular surface and joint structure congruity. However, to date there are no disease modifying medical therapies against PTOA. Increased recent understanding of the pathogenesis of the subchondral bone and synovial inflammation as well as that of chondrocyte mitochondrial dysfunction and apoptosis have led to the investigation of new therapeutics targeting these mechanisms to prevent or delay PTOA. This review discusses new advances in our understanding of cellular mechanisms underlying PTOA, and therapeutic approaches that are potentially effective in reducing the self-propagating cycle of subchondral bone alterations, inflammation, and cartilage degradation. Within this context, we focus therapeutic options involving anti-inflammatory and anti-apoptotic candidates that could prevent PTOA.