Understanding cartilage protection in OA and injury: a spectrum of possibilities

Abstract

Background: Osteoarthritis (OA) is a prevalent musculoskeletal disease resulting in progressive degeneration of the hyaline articular cartilage within synovial joints. Current repair treatments for OA often result in poor quality tissue that is functionally ineffective compared to the hyaline cartilage and demonstrates increased failure rates posttreatment. Complicating efforts to improve clinical outcomes, animal models used in pre-clinical research show significant heterogeneity in their regenerative and degenerative responses associated with their species, age, genetic/epigenetic traits, and context of cartilage injury or disease. These can lead to variable outcomes when testing and validating novel therapeutic approaches for OA. Furthermore, it remains unclear whether protection against OA among different model systems is driven by inhibition of cartilage degeneration, enhancement of cartilage regeneration, or any combination thereof. Main text: Understanding the mechanistic basis underlying this context-dependent duality is essential for the rational design of targeted cartilage repair and OA therapies. Here, we discuss some of the critical variables related to the cross-species paradigm of degenerative and regenerative abilities found in pre-clinical animal models, to highlight that a gradient of regenerative competence within cartilage may exist across species and even in the greater human population, and likely influences clinical outcomes. Conclusions: A more complete understanding of the endogenous regenerative potential of cartilage in a species specific context may facilitate the development of effective therapeutic approaches for cartilage injury and/or OA.

Experimental Therapeutics for the Treatment of Osteoarthritis

“…62,63 Models are performed in various animal species such as mice, rats, rabbits and dogs. 5,62,[64][65][66] Rodent models are broadly used. 63, [67][68][69][70] Approaches to induce OA differ ( Figure 2).…”

“…In regard to therapeutical targets in OA, several reviews of literature have recently been published which can be studied. [2][3][4][5][6][7][8][9][10] However, mesenchymal stromal cell (MSCs) or exosome-based approaches, interrelation of OA with the microbiome, novel strategies of improved viscosupplementation as well as the arising knowledge concerning the impact of micro RNAs (miRNAs) in the OA therapy are less addressed and hence, present a topic of this review. In view of the abundant novel literature related to these issues, this review remains mainly confined to most recent findings of the last three years.…”

Is Extracellular Vesicle-Based Therapy the Next Answer for Cartilage Regeneration?

“…Chondrocytes are surrounded by an extracellular matrix (ECM) they synthetize. Articular cartilage viscoelastic properties provide wear-resistant surfaces to the joint by improving the distribution of mechanical loads and moderating the friction between its surfaces (Sanchez-Adams et al, 2014;Lindahl, 2015;Bianchi et al, 2020;Masson and Krawetz, 2020). When injured or degenerating, articular cartilage is not able to restore its original organization because it has a very weak regenerative capacity.…”

“…When injured or degenerating, articular cartilage is not able to restore its original organization because it has a very weak regenerative capacity. The lost hyaline cartilage is replaced by fibrocartilage, but this reparative process is mechanically inadequate with a new cartilage lacking inherent functionality (Goldring et al, 2017;Lepage et al, 2019;Masson and Krawetz, 2020).…”

Creating a Pro-Regenerative Tissue Microenvironment: Local Control is the Key

“…Given the complexity of endogenous tissue regeneration mechanisms, it is not surprising that the outcomes of regenerative medicine therapies in human populations have been variable, as it is now known that they are highly impacted by genetics, age and co-morbidities, including diabetes, obesity and disfunctions of the immune system ( Fadini et al, 2020 ; Masson and Krawetz, 2020 ). Thus, for the clinical success of regenerative medicine, it will be important to develop and test promising therapies in disease-relevant animal models, including large animal models, that reflect elements of the heterogeneity of human populations ( Ribitsch et al, 2020 ).…”