Pathophysiology of osteoarthritis

Pathophysiology of osteoarthritis

Dr. Mohamed Hanafy

professor of rheumatology

Al Azhar University

In general, pathophysiology is a study of the changes of normal mechanical, physical, biochemical and biological functions, either caused by a disease, or resulting from abnormal syndrome. Pathology and pathophysiology often involve substantial overlap in diseases and processes, but pathology emphasizes direct observations, while pathophysiology emphasizes quantifiable measurements

Is OA primarily a disease of cartilage?

Under normal conditions, this matrix is subjected to a dynamic remodeling process in which low levels

of degradative and synthetic enzymes activities are balanced, where the volume of cartilage is maintained.

1) In OA cartilage, however, matrix degrading enzymes are overexpressed, shifting this balance in favor of net degradation.

2) As the disease progresses, however, reparative attempts are outmatched by progressive cartilage degradation.

3) Finally, fibrillation, erosion and cracking initially appear

in the superficial layer of cartilage and progress over time

to deeper layers, resulting eventually in large clinically

observable erosions.

Is OA simply a process of aging of cartilage?

It is anticipated that by the year 2030, 20% of adultswill have developed OA in Western Europe and North

America. OA is not only a common problem among the elderly population, but also it is becoming more widespread among younger people.

A critical question is whether OA is truly a disease or a natural consequence of aging.

New facts show that several differences between aging cartilage and OA cartilage have been described:

1) Although denatured type II collagen is found in both normal aging and OA cartilage, it is more predominant in OA.

2) OA and normal aging cartilage differ in the amount of water content and in the ratio of chondroitin-sulfate to keratin sulfate constituents.

3) A final but important distinction is that degradative enzyme activity is increased in OA, but not in normal aging cartilage

What molecules are responsible for degrading cartilage matrix?

The primary enzymes responsible for the degradation of cartilage are the matrix metalloproteinases (MMPs). These enzymes are secreted by both synovial cells and chondrocytes and are categorized into three general categories:

a) collagenases;

b) stromelysins;

c) gelatinases.

What factor(s) is/are responsible for inducing metalloprotease synthesis?

1) In OA inflammation appears to be related to the introduction of bone and cartilage breakdown products into the synovial fluid.

2) These products are

phagocytosed by cells in the synovium.

- IL-1 is a potent pro-inflammatory cytokines, which is capable of inducing chondrocytes and synovial  cells to synthesize MMPs.

- Furthermore, IL-1 suppresses not only the synthesis of type II collagen and proteoglycans, but also inhibits transforming growth factor-ß stimulated chondrocyte proliferation, and may also suppress attempts at repair in OA.

- In addition to these effects, IL-1m induces nitric oxide production, prostaglandin synthesis and chondrocyte apoptosis, which further contribute to cartilage deterioration.

• Possible Role of Nitric Oxide:

NO can be expressed after the activation of chondrocytes by cytokines (i.e., in association with inflammation). Once formed, NO may contribute to IL-1-induced degradation of cartilage, mainly by decreasing the synthesis of the extracellular matrix (ECM).

• Role of Prostaglandins:

Once formed, PGE2 increases the synthesis of stromelysin, a cartilage-degrading protein (MMP). PGE2 also has important pro-inflammatory properties and contributes to vasodilatation and pain in patients with OA.

• Role of Leptin:

Leptin alone or in combination with IL-1 enhanced the production of NO, PGE2, IL-6, and IL-8. Leptin has been shown to decrease chondrocyte proliferation and to increase production of proinflammatory cytokine IL-1, and destructive MMP-9 and 13 in human chondrocytes.

Recently

There is a debatable question about the pathophysiology of OA.

Does OA start in cartilage or in bone?

Although it is not yet clear whether it precedes or occurs subsequently to cartilage damage, the subchondral bone remodeling is an important feature in the pathophysiology of OA.

Studies in both human and animal models of OA support the concept that bone sclerosis could precede cartilage degradation and loss.

Histopathology is described in the subchondral bone and cartilage of rat (Wistar) knee joints treated with a single intra articular injection of mono-iodoacetate (MIA), to promote loss of articular cartilage similar to that noted in human OA and sacrificed at 1, 3, 5, 7, 14, 28,and 56 days post-injection.

1)Histologically, the early time points (days 17-) were characterized by areas of chondrocyte degeneration/necrosis sometimes involving the entire thickness of the articular cartilage in the tibial plateaus and femoral condyles. Changes to the subchondral bone, as evidenced by increased numbers of osteoclasts and osteoblasts, were noted at by day 7.

2) By 28 days, there was focal fragmentation and collapse of bony trabeculae with fibrosis and increased osteoclastic activity, and osteopenic changes.

3) By 56 days there were large areas of bone remodeling evidenced by osteoclastic bone resorption and newly formed trabeculae, with loss of marrow hematopoietic cells. Subchondral cysts and subchondral sclerosis were present.

It has been demonstrated that osteoblasts from sclerotic zones of subchondral OA, downregulated aggrecan synthesis and upregulated metalloproteases expression by chondrocytes.

It was observed that OA osteoblasts induce bone sclerosis through abnormal IGF-I and uPA (plasminogen activator) dependent bone remodeling.

OA osteoblasts are resistant to parathyroid hormone (PTH) stimulation, a situation that can also contribute to abnormal bone remodeling and bone sclerosis in OA.

OA osteoblasts produce an abnormal homotrimeric type I collagen with a low affinity for calcium, responsible for the low mineralization of matrix of OA subchondral bone.

Studies revealed that the hepatocyte growth factor found in articular cartilage is produced by osteoblast, defused into the cartilage and may be implicated in the progression of OA. These results reinforced the idea of a role played by osteoblast in cartilage fibrillation.

There is a clear demonstration of increased bone activity as seen by radiographic studies and MR imaging before cartilage degradation.

Early subchondral changes include redistribution of blood supply with marrow hypertension, edema and probably micro-necrosis.

All these findings suggest that abnormal osteoblasts play a critical role in subchondral bone sclerosis.

Can cartilage repair itself?

Regulation of cartilage synthesis and Degradation

1)IL-1 and TNF – alpha promote cartilage degradation by enhancing:

. MMP synthesis

. Prostanoid synthesis

. Chondrocyte apoptosis

2) IL-1 receptor antagonist (IL-1 ra) and TIMP can counteract these degradative processes

3) Growth factors promote cartilage repair by :

. Enhancing expression of IL-1ra, TIMP, type II collagen and proteoglycans

. Downregulating expression of IL-1 receptor

. Enhancing chondrocyte proliferation