Cartilage
Body Fluids and the Extracellular Matrix
In healthy adults, more than 50% of body weight is said to consist of fluids. This is because both the inside and outside of cells are aqueous environments. The cytoplasm within cells is composed primarily of water, and the spaces outside the cells and between cells are also filled with water. One-third of all body fluids is extracellular fluid (ECF), which contains ions, nutrients, hormones, and waste products, thereby supplying nutrients to cells and transmitting signals. Plasma—the fluid component of blood—as well as interstitial fluid and lymph are all classified as extracellular fluids. This ECF forms a water-like environment in which cells appear to be "floating."Then, what is the extracellular matrix (ECM)? The ECM is a semi-solid, jelly-like structure that surrounds the cells. Unlike water-based ECF, it is composed of substances such as proteins, glycoproteins, and proteoglycans, which support and maintain cellular structures. In other words, while the ECF, being primarily liquid, facilitates the exchange of substances between cells and maintains cellular homeostasis through ion regulation, the ECM helps maintain the shape and structural integrity of the cells.
The ECF is a freely moving fluid component, consisting of plasma elements that have leaked out of blood vessels and flow between cells. In contrast, the ECM is composed of proteins and polysaccharides that are directly produced and secreted by cells. These substances bind to the cell surface and absorb water like a sponge, forming a gel-like structure that supports and anchors cells in defined spaces. Moreover, the proteins in the ECM that are connected to the cell surface also help the cell interact with its surrounding environment and neighboring cells.
One of the major components of the ECM that provides structural support, elasticity, and strength to tissues is glycosaminoglycans (GAGs), which we have discussed earlier. The ECM contains fibrous proteins such as collagen and elastin that maintain tissue strength and structure, glycosaminoglycans—disaccharide chains made of repeating modified sugars that bind to protein peptides—and glycoproteins, which consist of both sugar and protein components (though the protein proportion is much greater).
Most of these biomolecules are attached to a protein called fibronectin, often referred to as the glue of the ECM. Fibronectin, in turn, attaches to integrin, a receptor protein that spans the cell membrane, thereby anchoring the ECM to the cell. Among the materials that make up the ECM—such as collagen, fibronectin, laminin, and integrin—many are glycoproteins involved in cell adhesion and signal transduction. When epithelial cells, like skin or vascular endothelial cells, exist around connective tissue, a unique form of ECM called the basement membrane forms a thin but strong layer that acts as a nearly impenetrable barrier even against minor damage.
Connective Tissue and Cartilage
Connective tissue, which connects and supports tissues, is a broader concept that includes the ECM. The ECM is the critical component that enables connective tissue to function properly. The cells of connective tissue—such as fibroblasts, chondrocytes, and osteocytes—produce, secrete, and maintain the ECM. In the case of articular cartilage, the chondrocytes, which are the main cells of cartilage, directly synthesize and maintain the ECM, and the function of cartilage is closely tied to the integrity of its ECM. Since we have already examined the GAGs involved in cartilage, let's now explore how they work and their underlying mechanisms.
These days, it's not uncommon to see people undergoing artificial joint surgeries, and the number of people suffering from arthritis seems to be increasing. It's a natural phenomenon as both I and those around me grow older, but I’ve always been curious about how joints and cartilage function. So let’s take a detailed look at the mechanisms behind them to better understand the remarkable roles and functions of GAGs in this context.
Structure of cartilage
Cartilage is a white, smooth, glossy connective tissue that covers areas where bones meet. Internally, cartilage is divided into three main layers, with collagen fibers arranged in different directions in each. The outermost layer, the Surface Zone, is where friction occurs most, and strong shear forces arise when bones slide against each other during joint movement. To resist these forces and disperse shock, collagen fibers are aligned horizontally, parallel to the joint surface. This alignment prevents cartilage from tearing easily. This layer is rich in hyaluronic acid and serves a lubricating function.
The Deep Zone, the innermost layer, directly bears mechanical pressure. Collagen here is arranged vertically like pillars to provide compressive strength. This layer contains fewer chondrocytes and the highest concentration of proteoglycans, which retain water. The middle Zone, which bridges the superficial and deep zones, contains irregularly arranged collagen to distribute pressure evenly. There is also a Calcified Zone at the bottom, which connects directly to the bone.
Cartilage is truly a remarkable tissue. It's fascinating how the knees can bear a load of nearly 100 kg and how cartilage between bones absorbs and distributes the tremendous pressure from walking or running. Once fully developed, cartilage has very limited regenerative capacity, making it a tissue that must be used with care throughout life.
The secret to cartilage’s impressive support lies in its extracellular matrix. Mechanical loads from above and shear forces on cartilage surfaces are primarily managed by the collagen and aggrecan aggregates within the ECM. Simply put, collagen forms a robust mesh structure across the ECM. Aggrecan aggregates, with their remarkable water-retention capacity, compress under load as aggrecan molecules come closer together and expel water. When the pressure is removed, they spring back to their original form and reabsorb water, cushioning the cartilage. Together, collagen and aggrecan aggregates form a protective mesh.
Components of cartilage
Articular cartilage is composed solely of chondrocytes. Its ECM is filled with a network of type II collagen and massive aggrecan aggregates—proteoglycans bound to hyaluronic acid. Though chondrocytes only account for about 2% of cartilage volume, the ECM makes up about 65–80%.[1]
Aggrecan is found in joints, hyaline cartilage, elastic cartilage, and fibrocartilage—distributed in joints, ribs, nasal passages, the larynx, outer ear, and epiglottis. It is a proteoglycan made of GAGs like chondroitin sulfate (CS) and keratan sulfate (KS) bound to a protein peptide. With around 100 CS and 25–50 KS chains, aggrecan resembles a densely packed toilet brush(most people picture a bottle brush..though..). When multiple aggrecan molecules attach along a long hyaluronic acid filament, they form a giant aggrecan aggregate. These aggregates tangle with collagen fibers to create a gel-like semi-solid structure.
Function of aggrecan
Aggrecan's key feature is its extraordinary ability to retain water, which provides resistance to compression. All three GAGs in aggrecan aggregates are highly hydrophilic. CS and KS, in particular, acquire strong negative charges via sulfation, attracting counterions and drawing in water to maintain cartilage elasticity and absorb shock. Picture aggrecan trapped between dense collagen meshes: in a relaxed state, the sulfated GAG chains expand and push apart, drawing in water until restrained by the surrounding collagen network, at which point equilibrium is reached. When cartilage is compressed and water is expelled, the aggrecans move closer, increasing swelling potential. Once the pressure is relieved, aggrecan rapidly rebounds like a spring, reabsorbing water and restoring balance. The diagram below illustrates this.
The reason articular cartilage can withstand loads several times greater than human body weight lies in its structure, which makes it difficult for water to escape. This water acts like a cushion, effectively dispersing external forces. Unlike bones and general connective tissue ECMs, cartilage lacks nerves, blood vessels, and lymph nodes. Instead, synovial fluid and water in the extracellular matrix provide necessary nutrients and remove waste. As pressure is applied and released, water circulates—making proper exercise crucial for cartilage health. While collagen in bones and other connective tissues is typically tough type I, cartilage contains type II collagen, which has high elasticity and flexibility to absorb repeated shock. Even within cartilage tissue, collagen is layered and aligned differently to suit various roles, protecting the cartilage accordingly.
Homeostasis of cartilage and osteoarthritis
The balance between synthesis and degradation of ECM components by chondrocytes maintains cartilage homeostasis. Disruption of this balance leads to osteoarthritis (OA). [2] Injuries, repetitive friction, or microfractures can cause collagen and proteoglycans to wear down, releasing small fragments known as wear debris. These are recognized as foreign substances and may trigger immune responses. Macrophages become activated to remove them and secrete inflammatory cytokines such as TNF-α, IL-1, and IL-6 in the process. The problem is that these cytokines activate matrix-degrading enzymes like MMP and ADAMTS, which cleave collagen and degrade aggrecan, damaging the extracellular matrix. Ongoing inflammation also inhibits the synthesis of collagen type II, the primary structural protein in cartilage. Continued inflammation and stress disrupt homeostasis, eventually leading to chondrocyte death, thinning of the cartilage, and progression to osteoarthritis.
Other causes of cartilage inflammation include aging, obesity, metabolic disorders like diabetes, infections, and reactive oxygen species (ROS). It’s also worth remembering that obese individuals release large amounts of inflammatory cytokines from fat cells and diabetic patients experience increased inflammation due to high blood sugar. Treatments for arthritis include TNF-α inhibitors, IL-1 inhibitors, corticosteroids (which have strong anti-inflammatory effects), and nonsteroidal anti-inflammatory drugs (NSAIDs).
[1] The Basic Science of Articular Cartilage
[2] Histology, Chondrocytes
https://www.ncbi.nlm.nih.gov/books/NBK557576/
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