Epigenetics and Cartilage Regeneration

*Samina Hyder Haq, Iqraa Haq, Atheer Ali Alsayah, Abir Alamro and Amani AlGhamedi* 

## **Abstract**

Regenerative cartilage therapy has great potential for the treatment of debilitating diseases such as osteoarthritis and rheumatoid arthritis. Recent advances in the field of epigenetics have enabled us to understand more clearly the role of micro RNAs, DNA methylations and histone modification in disease progression, as well as its potential role in disease prevention. However, a thorough understanding of the external dietary and environmental factors that could affect the epigenetic events could be the key to unravelling novel therapeutic strategies for these diseases. There is, therefore, a need for identifying certain dietary or environmental factors that could change this downward epigenetics signalling cascade, stop or retard cartilage degradation and promote cartilage regeneration.

**Keywords:** cartilage regeneration, DNA methylations, epigenetics, therapeutic dietary supplements, DNMT inhibitors

## **1. Introduction**

 Articular cartilage is an aneural, avascular, alymphatic specialized fibrous connective tissue which covers the articulating surface of synovial joints. This is characterized by a small number of morphologically distinct populations of chondrocytes, which are primarily responsible for production, organization and maintaining the extensive network of an extracellular matrix. The balance between the hydration of matrix proteoglycans (PGs) and the resistance offered by the extensive network of the fibrous structure of the collagen provides the hydrodynamic load-bearing properties of articular cartilage, which is critical for joint movements and smooth transmission of mechanical compression across the joint. As articular cartilage is originally derived from the hyaline cartilage template, it is also classified as permanent hyaline cartilage. After the original phase of cartilage production, differentiation and resorption and closure of growth plate cartilage at puberty, it remains as a part of bone throughout the adult life. It is divided into four distinct horizontal layers: the superficial, transitional, deep and calcified cartilage layers (**Figure 1**).

 The thin superficial zone protects the deeper layers from shear stress and injury and makes up 10–20% of articular cartilage thickness. This layer is characterized by small flattened disc-shaped chondrocytes, comparatively low proteoglycan content and densely packed layers of uniformly formed collagen fibres, which gives the characteristic hyaline opacity to cartilage. This layer is in direct contact to synovial fluids and is responsible for most of the tensile strength of the cartilage as well as

 takes the direct brunt of inflammatory cytokines. It is well documented that the chronic inflammation in joints in osteoarthritis (OA) patients is due to synovial macrophages and high inflammatory cytokines that initiate the aggregenase, MMPs and other destructive enzymes. Immediately below the superficial zone is the middle or transitional layer which provides the functional bridge between the superficial and deep layers. The middle layer comprises of 40–60% of the total cartilage volume. In this layer, the chondrocytes attain a more rounded or spherical shape, the contents of proteoglycans increase, and thicker collagen fibres provide an oblique transitional network intermediate between the tangential superficial and radial deep layers. The deep layer is characterized by relatively mature rounded chondrocytes arranged in longitudinal columns, high proteoglycan contents, the largest diameter collagen fibrils in a radial disposition and the lowest water concentration. This zone represents approximately 30% of the total cartilage volume. The calcified layer is characterized by rounded hypertrophic chondrocytes surrounded by large clear lacunae. This is the area where the chondrocytes reach their terminal hypertrophic stage and the cartilage is ultimately being replaced by bone.
