Pathomechanisms of Posttraumatic Osteoarthritis: Chondrocyte Behavior and Fate in a Precarious Environment

Abstract

Traumatic injuries of the knee joint result in a wide variety of pathomechanisms, which contribute to the development of so-called posttraumatic osteoarthritis (PTOA). These pathogenetic processes include oxidative stress, excessive expression of catabolic enzymes, release of damage-associated molecular patterns (DAMPs), and synovial inflammation. The present review focuses on the underlying pathomechanisms of PTOA and in particular the behavior and fate of the surviving chondrocytes, comprising chondrocyte metabolism, regulated cell death, and phenotypical changes comprising hypertrophy and senescence. Moreover, possible therapeutic strategies, such as chondroanabolic stimulation, anti-oxidative and anti-inflammatory treatment, as well as novel therapeutic targets are discussed.

Keywords: CSPC; DAMP release; anabolism; catabolism; cell death; chondrocytes; oxidative stress; posttraumatic osteoarthritis; synovial inflammation; therapy.

Figure 1

Cartilage trauma leads to oxidative stress and DAMP release. These mediators further trigger regulated chondrocyte death, synovial response and complement activation, which result in the production of catabolic enzymes and pro-inflammatory factors—key drivers of ECM degradation. These pathophysiologic conditions also promote phenotypical changes of the chondrocytes, comprising hypertrophy and senescence. Black lines = directly trauma-related; blue lines = chondrocytes-related; green lines = synovial cell-related; red lines = directly ROS/DAMP/complement-related.

Figure 2

Catabolic, anabolic, hypertrophic and senescence-associated markers in chondrocytes health and disease. The illustration comprises secreted (i.e., MMPs, chemokines, cytokines) as well as intracellular master regulators and effectors (RUNX2, SOX9 p14^ARF and p16^INK4a). Moreover, regulatory growths factors were included but parenthesized as they contribute to the hypertrophic and chondroanabolic phenotype, respectively, but are usually not considered as markers; AP = alkaline phosphatase.

Figure 3

Therapeutic targeting of posttraumatic pathomechanisms. The behavior and fate of chondrocytes might be modulated on different levels: upstream, the attenuation or elimination of harmful triggers and mediators (indirect modulation); downstream, addressing the cellular response itself by selective inhibition of unwanted processes or chondroanabolic stimulation (direct modulation).