madman
Super Moderator
Osteoarthritis (OA) is a widespread condition with significant impact, driven by cartilage injuries leading to OA progression. Effective cartilage regeneration methods are crucial, but current treatments lack reliability. This is due to a fundamental lack of understanding of cartilage regeneration failure. Research into these mechanisms is vital for patient treatment decisions and future therapy development. The review examines hypotheses behind cartilage regeneration failure and associated therapeutic strategies, offering insights into current and potential OA treatments.
Key Takeaways:
Cellular Failure
Mechanical Failure
Inflammatory stress
Metabolic stress
● Articular cartilage is avascular and receives oxygen and nutrients from synovial fluid through diffusion.
● Oxygen tension in cartilage is lower than in most tissues, with levels around 5% at the surface and 1% in deeper regions.
● Chondrocytes, the cells in cartilage, primarily rely on glycolysis for energy, with only about 25% of energy coming from oxidative phosphorylation.
● Proper balance of oxygen and glucose uptake, along with redox control from oxidative phosphorylation, is crucial for chondrogenesis, differentiation, and cell survival.
● Chondrocytes use unique molecular mechanisms like hypoxia-inducible factor 1 (HIF1) regulation, mitochondria dynamics, redox control, and metabolic regulation to adapt to the low-oxygen and low-nutrient microenvironment.
● Normal mechanical loading maintains metabolic homeostasis, but cartilage damage disrupts oxygen tension control, leading to increased energy demand and compromised microenvironment.
● Metabolic shift during cartilage damage involves dysregulated glycolysis, lactate accumulation, acidification, inhibition of matrix synthesis, and cartilage degeneration.
● Insufficient oxygen and glucose affect ATP formation, limiting cell function and survival, disrupting mitochondrial homeostasis, and triggering reactive oxygen species (ROS)-induced stress.
● ROS-induced stress activates survival pathways like AMP-activated protein kinase (AMPK) and mTOR signaling, as well as cytokine response, affecting matrix remodeling and cell survival.
● Chondrocytes can survive acute metabolic changes and return to homeostasis after stress resolution, but extensive cartilage defects lead to irreversible degeneration.
● Irreversible effects include a shift from aggrecanase activity to matrix metalloproteinase (MMP) activity, accelerating proteoglycan and collagen type II turnover.
● Aging, obesity, and type II diabetes disrupt metabolic homeostasis and negatively impact cartilage regeneration.
● Current research explores various approaches and therapeutic solutions to target cartilage metabolism for better regeneration outcomes.
The conclusion emphasizes that multiple hypotheses explain cartilage regeneration failure, leading to degeneration and osteoarthritis. Various stressors are involved, and the review aimed to connect therapeutic strategies with these ideas. However, current treatments haven't consistently achieved full cartilage regeneration, suggesting a need to target different factors as diseases progress. Future trials should focus on specific hypotheses and deepen our understanding of cartilage biology and regeneration failure. Even unsuccessful trials can guide the development of next-gen treatments amid the complex landscape of cartilage regeneration.
Key Takeaways:
Cellular Failure
- Low cell density and low proliferative capacity of mature chondrocytes are believed to be the main factors limiting cartilage's regenerative potential.
- Articular chondrocytes' cell density and in vitro proliferative capacity decrease with age, particularly after 30 to 40 years.
- Cartilage cell density also decreases in post-traumatic osteoarthritis.
- Chondrocyte apoptosis is associated with cartilage degeneration, but it's unclear whether it is a cause or result of the disease.
- Smaller mammals tend to have higher chondrocyte density and better cartilage regeneration capacity compared to larger mammals.
- Healthy and osteoarthritic cartilage contains cells with progenitor-like characteristics, which have high proliferation capacity and chondrogenic potential.
- Progenitor-like cells, despite their potential, generally fail to efficiently regenerate cartilage defects.
- Strategies targeting the delivery or recruitment of competent cells into cartilage defects are supported for enabling cartilage regeneration.
Mechanical Failure
- Mechanical changes within a joint contribute to cartilage loss through trauma or chronic degeneration.
- These changes alter the load-bearing contact area of the joint, leading to abnormal joint loading, release of alarmins, activation of fibroblasts and macrophages, and production of pro-inflammatory mediators, causing cartilage injury.
- Pathological changes involve breakdown of the extracellular matrix, fibrillation of the collagen network, and synovial inflammation.
- Abnormal loading patterns can be worsened by changes in the subchondral bone, reducing the regenerative capacity of cartilage.
- Age-related metabolic changes and stiffness in the cartilage matrix further compound the cumulative mechanical changes, resulting in larger biological abnormalities.
- Preventing subchondral bone sclerosis could protect the regenerative potential of pathological cartilage.
- Chondrocyte response to mechanical conditioning depends on factors like loading magnitude, frequency, and duration.
- Physiological cyclic compression can enhance chondrogenesis, extracellular matrix production, and tissue regeneration.
- Mechanical stimulation is crucial for activating signaling molecules associated with chondrocyte metabolism and cartilage homeostasis.
- Different approaches to restoring appropriate mechanical loading have been integrated into cartilage regenerative strategies.
Inflammatory stress
- Inflammatory stress negatively affects the functioning of chondrocytes and cartilage regeneration.
- Inflammatory stress impairs chondrocyte viability, matrix synthesis, and promotes matrix catabolism.
- The inflammatory process involves various inflammatory mediators, making it challenging to target specific signals for therapeutic purposes.
- Potential therapeutic targets for inhibiting inflammation and promoting cartilage regeneration include protein kinases, sirtuins, neurotrophins, alarmins, pro-inflammatory cytokines, and matrix-degrading enzymes.
- However, none of these targets have been clinically proven effective for cartilage regeneration.
- Strategies for addressing cartilage regeneration are depicted in Fig. 3 and discussed in the following section.
Metabolic stress
● Articular cartilage is avascular and receives oxygen and nutrients from synovial fluid through diffusion.
● Oxygen tension in cartilage is lower than in most tissues, with levels around 5% at the surface and 1% in deeper regions.
● Chondrocytes, the cells in cartilage, primarily rely on glycolysis for energy, with only about 25% of energy coming from oxidative phosphorylation.
● Proper balance of oxygen and glucose uptake, along with redox control from oxidative phosphorylation, is crucial for chondrogenesis, differentiation, and cell survival.
● Chondrocytes use unique molecular mechanisms like hypoxia-inducible factor 1 (HIF1) regulation, mitochondria dynamics, redox control, and metabolic regulation to adapt to the low-oxygen and low-nutrient microenvironment.
● Normal mechanical loading maintains metabolic homeostasis, but cartilage damage disrupts oxygen tension control, leading to increased energy demand and compromised microenvironment.
● Metabolic shift during cartilage damage involves dysregulated glycolysis, lactate accumulation, acidification, inhibition of matrix synthesis, and cartilage degeneration.
● Insufficient oxygen and glucose affect ATP formation, limiting cell function and survival, disrupting mitochondrial homeostasis, and triggering reactive oxygen species (ROS)-induced stress.
● ROS-induced stress activates survival pathways like AMP-activated protein kinase (AMPK) and mTOR signaling, as well as cytokine response, affecting matrix remodeling and cell survival.
● Chondrocytes can survive acute metabolic changes and return to homeostasis after stress resolution, but extensive cartilage defects lead to irreversible degeneration.
● Irreversible effects include a shift from aggrecanase activity to matrix metalloproteinase (MMP) activity, accelerating proteoglycan and collagen type II turnover.
● Aging, obesity, and type II diabetes disrupt metabolic homeostasis and negatively impact cartilage regeneration.
● Current research explores various approaches and therapeutic solutions to target cartilage metabolism for better regeneration outcomes.
The conclusion emphasizes that multiple hypotheses explain cartilage regeneration failure, leading to degeneration and osteoarthritis. Various stressors are involved, and the review aimed to connect therapeutic strategies with these ideas. However, current treatments haven't consistently achieved full cartilage regeneration, suggesting a need to target different factors as diseases progress. Future trials should focus on specific hypotheses and deepen our understanding of cartilage biology and regeneration failure. Even unsuccessful trials can guide the development of next-gen treatments amid the complex landscape of cartilage regeneration.
