The Pathophysiology of Osteoarthritis

Osteoarthritis is often described as a condition resulting from wear-and-tear on joints, but the pathophysiology of this condition is much more complex than that. It involves a series of changes at the cellular level that lead to damaged cartilage, synovial membranes, and bones.

Also known as degenerative joint disease, osteoarthritis is the most common form of arthritis and accounts for roughly 59% of all arthritis cases. It is mostly found in the hands, hips, and knees.

Articular Cartilage

Articular cartilage, also known as hyaline cartilage, is a type of cartilage found on the ends of bones, where they meet and form joints. This type of cartilage is responsible for healthy movement—a healthy level of articular cartilage allows bones to glide over each other with ease. Its structure is a network mostly made of water, collagen, and glycosylated proteins. Highly specialized cells known as chondrocytes are also found within this network.

Articular cartilage cannot regrow on its own and is devoid of blood vessels, nerves, and lymphatics. The capacity of chondrocytes to regenerate surrounding cartilage is limited.

Damage to the articular cartilage comes with four changes. One is matrix fibrillation, during which the network of cartilage, known as the matrix, begins to soften, leaving clefts or spaces between the cells. The cartilage then develops fissures and ulcers, and the joint surface begins to disintegrate.

In osteoarthritis, the health of articular cartilage plays a pivotal role in how well joints function. Damage to the articular cartilage occurs in three stages:

• Stage 1: The proteins in the cartilage begin to break down. They transform from full proteins into polypeptides and amino acids.
• Stage 2: Fibrillation and erosion take place. Fragments of collagen and proteins begin to leak into the synovial fluid, which is designed to reduce friction between joints.
• Stage 3: The body’s inflammatory response to the first two stages triggers further damage to the cartilage.

How Damage Occurs

When the inflammatory response begins, it releases interleukin-1, a cytokine that contributes to cartilage degradation. When interleukin-1 is released, it promotes further cartilage damage by controlling the bioavailability to specific proteases. It does this by encouraging specific enzymes to break down the protein within the joint into smaller polypeptides and amino acids. The same is the case for another cytokine, tumor necrosis factor-alpha (TNF-alpha), which can stimulate certain enzymes known as matrix metalloproteinases (MMPs) that can severely damage the matrix of the joint.

Other enzymes, known as collagenases, can also break down collagen and damage joint health. Stromelysin, or MMP-3, is found in high amounts in those with osteoarthritis because this enzyme is also a key player in the degeneration of the part of the joint matrix that doesn’t include collagen.

Conditions affecting other parts of the body such as obesity, joint instability, misalignment of joints, and trauma can contribute to the degradation of joint systems in those with osteoarthritis.

Synovial Membranes

The synovial membrane is a connective tissue lining the joints, and it produces synovial fluid. In the people with osteoarthritis, when the cartilage begins to break down and makes its way into the synovial fluid, it leads to inflammation of the synovial membrane.

This is because synovial macrophages, the cells that induce the production of pro-inflammatory cytokines, can elicit an inflammatory immune response to pieces of stray cartilage within the synovial fluid. This then leads to further cartilage breakdown because over time, as the joint loses its cartilage, the synovial fluid begins to leak out of the joint, resulting in a permanent thinning and loss of viscosity.

Less synovial fluid cushioning the movement of the joint also means bone-on-bone friction and more damage. When the synovial fluid becomes thin enough, inflammatory substances begin to directly touch or come into contact with nerve cells within the joint, leading to pain. The more synovial fluid is lost, the faster the cartilage deteriorates.

Bones

When bones lose the protective cushion of cartilage due to damage from osteoarthritis, they begin to rub together. The joints can then become stiff and less able to tolerate the impact of regular movement, putting more stress on the remaining intact cartilage as the disease progresses. When there is no longer any cartilage left in the joints, bone-on-bone friction occurs.

Bone then undergoes remodeling, a process that includes bone erosion, cartilage degeneration, and the formation of bone spurs. The remodeling process can drive further impairment of joint function.

Bone Spurs and Cysts

Osteophytes, or bone spurs, begin to develop. Bone spurs are smooth growths of bone, and although they don’t typically cause pain, they are associated with painful symptoms if they begin to irritate tissues they come in contact with.

Osteoarthritis can also lead to the development of bone cysts, which are fluid-filled sacs that form inside damaged joints. Bone marrow lesions are also present in osteoarthritis and can be attributed to remodeling caused by improper joint movement, load-bearing, and mechanical overload of damaged joints.

Subchondral Bone

In those with osteoarthritis, changes in the bone supporting the joint cartilage (subchondral bone) occur. Subchondral bone is found in most joints, including the ones affected by osteoarthritis, such as the knees and hips. It can also be found in small joints in the hands and feet.

Typically, bone marrow lesions and bone cysts occur in the subchondral bone. Since damage to the articular cartilage is the main driver of osteoarthritis, those changes in the subchondral bone haven't received as much attention in the past. They are now, however, considered a vital component in the pathogenesis of osteoarthritis. In people with osteoarthritis, the subchondral bone is softened and discolored because of the remodeling process.

Treatment

Currently, treatment options for osteoarthritis are limited. The damage done to joints is irreversible, and thus, treatment of osteoarthritis usually involves managing symptoms.

Medications

Symptoms such as pain in the affected joints and tenderness can be aided with the use of pain medications such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and other chronic pain medications such as Cymbalta (duloxetine).

Injections

Cortisone injections are used to help relieve pain, but corticosteroid medication can lead to further damage to the bones connecting at the joint. This may be because they can inhibit the body's ability to absorb calcium and lead to the weakening of bones and bone loss. In people with osteoarthritis, the weakening and breakdown of bones can drive the progression of the disease.

Lubrication injections are done using hyaluronic acid and aim to provide more cushion to help lessen the impact on the damaged joint.

Physical Therapy

Certain exercises in physical therapy can help build up the muscles that surround a damaged joint, which can lessen the strain felt in the area and relieve pain. Occupational therapy can also be used to help a person with osteoarthritis cope with their condition by changing the way they perform everyday tasks to avoid putting unneeded pressure on the damaged joints.

Surgery

Surgical treatments are available when other interventions don’t help alleviate the painful symptoms of osteoarthritis, including:

• Bone realignment: Otherwise known as an osteotomy, this surgery is performed by adding or removing a wedge of bone. This is done in cases where one side of the body is affected more than the other, such as in the knees, and balancing load-bearing could help alleviate pressure on the damaged joint.
• Joint replacement: In the most serious cases, a surgeon may recommend a full joint replacement. This is done by removing certain surfaces of the damaged joint and replacing them with plastic and metal parts. As artificial joints may eventually need replacement, this type of surgery is typically only done in serious cases.

New Therapies  

A new understanding of the pathophysiology of osteoarthritis has led to studies of other promising treatment options. Due to the role that MMPs play in the progression of the disease, researchers are developing new medications designed to inhibit these effects. Targeting articular cartilage degeneration specifically, anabolic medications such as Spriferim and BMP-7 have shown promise for repairing and rebuilding cartilage. Anti-catabolic medications, specifically MMP inhibitors, are also being explored as a viable option for those with osteoarthritis because of their ability to stall cartilage degeneration.

Another treatment option being explored is regenerative therapy using stem cells. Although the stem cells injected into the affected joint tend to disappear in a short amount of time, the immunomodulatory effects that often lead to a worsened case of osteoarthritis were found to be long-lasting. The therapy was also found to improve the biomechanics of joints affected by arthritic conditions and delay the narrowing of the affected joints.

Promising treatments using bisphosphonates are also in the works, but they may only work for a specific group of osteoarthritis patients. Bisphosphonates are medications designed to slow down the loss of bone density. People with osteoarthritis typically experience bone thickening accompanied by lesions and bone spurs. Some saw a decrease in bone marrow lesions after a six-month trial. This type of medication may be useful for those who have bone marrow lesions and are in the early stages of osteoarthritis.

There has also been a new treatment designed to neutralize an osteolytic protease that may encourage the loss of calcium in bones. Animal trials have found this to be effective at slowing down bone and cartilage degeneration. More research is needed to determine whether or not this type of neutralization will work for humans.

Since osteoarthritis causes an inflammatory immune response, anti-cytokine therapy has also been explored as a promising new method for treatment. This type of medication would hinder the immune response or cytokine production within the joints to help reduce inflammation that could lead to swelling and pain in the affected area. Pro-inflammatory signaling targeting may also be an effective new treatment option to help reduce inflammation. Although these therapies will not cure osteoarthritis or help rebuild lost cartilage, they could help with managing pain.

With the advancement of understanding, new treatment options for osteoarthritis can begin to provide hope to those with the condition.