Osteoarthritis (OA) is the most common joint disorder and the major cause of disability in the adult population. The
pathophysiology of the disease is characterized by progressive loss of articular cartilage, cartilage calcification,
osteophyte formation, subchondral bone remodeling, and mild to moderate inflammation of the synovial lining.
Symptoms include joint pain, tenderness, stiffness, inflammation, and creaking of the joints. Conventional treatment is focused on pain reduction using NSAIDs, local injections of glucocorticoid or hyaluronan, and in severe bone-onbone cases, joint replacement surgery.
Although cartilage destruction is the hallmark of OA disease, changes in the periarticular tissues, including the
subchondral bone, ligaments, tendons, menisci, and the synovial membrane is also involved. Simple ‘wear and
tear’ due to excessive use as the underlying cause of osteoarthritis is somewhat of an outdated explanation for the
role of mechanical overload/injury in osteoarthritis development.
Chondrocytes are the single cell within cartilage that is
responsible for developing and maintaining the cartilage
matrix. It synthesizes and secretes the collagen which is
the backbone of the cartilage matrix and proteoglycans
which functions as the cushion of the joint. When there is
cartilage damage, the chondrocyte will synthesize new
molecules to repair the damage. However, if there is too
much damage, it will work in a disruptive way. Cartilage
homeostasis is carefully balanced by metabolic and
catabolic pathways to maintain the extracellular matrix
structure and function throughout the articular cartilage
zones. Mechanical overloading, age-associated changes
in chondrocyte function, and disturbed cytokine activities
may all initiate extracellular matrix degradation and
contribute to the onset and progression of articular
cartilage deterioration resulting in osteoarthritis.
Joint inflammation due to joint trauma, mechanical overload, and overuse results in the remodeling of the subchondral bone, upregulation of matrix-degrading enzymes and chondrocyte phenotypic changes which lead to the development and progression of osteoarthritis. The joint injury can cause changes in the periarticular tissues which destabilizes the joint thus causing mechanical stress to the cartilage tissue. These periarticular tissues include subchondral bone, ligaments, tendons, menisci, and synovial membranes. Other factors that influence the disease process are those that can cause joint inflammation or mechanical overload such as aging, genetic predisposition, abnormal biomechanics, obesity, and comorbidities such as cardiovascular disease, metabolic syndrome, and diabetes.
Cartilage Matrix Micro-Cracks and Joint Pain
The earliest change in the development of osteoarthritis is the loss of negatively charged polysaccharide molecules
in the cartilage which results in increased water content and swelling of the cartilage matrix. The swelling of the
cartilage matrix causes micro-cracks in the superficial zone. As the disease progresses, exfoliation of fragments of
cartilage and deep fissures extending into the deeper cartilage layers leads to exposure of the underlying zones of
calcified cartilage and subchondral bone.
Further mechanical stress and exacerbation of naturally occurring pores in the subchondral bone can also produce
micro-cracks that provide conduits for vascular invasion into the calcified zone and enable diffusion of small
inflammatory molecules including cytokines and chemokines into the calcified zone.
In addition to cartilage damage, the subchondral bone undergoes remodeling with the additional growth of blood vessels (red) which also contains osteoblasts, osteoclasts, and sensory nerves (green) as well as the
diffusion of small inflammatory molecules. Such remodeling induces hypertrophic-like changes in chondrocytes and causes the expansion of the calcified zone. The expansion of the calcified zone leads to loss or thinning of the superficial zones. These hypertrophic-like chondrocytes also produce
proangiogenic factors, including VEGF, that promotes further vascular penetration to the calcified zone at the sites of micro-cracks and fissures, accompanied by sensory and sympathetic nerves resulting in joint pain and progressive loss or thinning of the superficial zones.
Cytokine and Enzyme-Mediated Cartilage Destruction
The development of osteoarthritis is highly dependent upon the upregulation of specific matrix-degrading enzymes. The major protagonists of cartilage degradation are the metal-dependent matrix metalloproteinase (MMP), disintegrin, and metalloproteinase with thrombospondin motifs (ADAMTS) families. Damaged cartilage tissue, inflamed synovium, and other injured joint tissues release cytokines, chemokines, alarmins, DAMPs, adipokines, and other mediators into the synovial fluid. These mediators increase chondrocyte production of matrix metalloproteinases (MMPs) which breaks down the cartilage collagen network and weakens the biomechanical function of the articular cartilage.
The synovium is also a source of degradative enzymes, including MMPs and aggrecanases that can directly degrade
the cartilage matrix causing the degradation of the collagenous and proteoglycan networks. The products of
cartilage matrix breakdown along with damage-associated molecular patterns (DAMPs) secreted by chondrocytes
also act on the adjacent synovial tissue to induce inflammation and the release of pro-inflammatory products,
including cytokines and reactive oxygen species that feedback on the chondrocytes to enhance the catabolic state
amplifying a vicious cycle of cartilage break down.
Chondrocyte Hypertrophy and the Bone-on-Bone Condition
Although chondrocytes rarely divide in the healthy tissue and appear relatively ‘quiescent’, they are extremely
mechanosensitive. Excessive mechanical loading on the chondrocytes activate the cell-surface mechanosensors
and induces hypertrophic-like phenotypic changes in chondrocytes. Hypertrophic chondrocytes trigger extracellular
matrix mineralization, blood vessel invasion, and the recruitment of chondroclasts/osteoclasts in the articular
cartilage. Chondroclasts/osteoclasts gradually degrade the cartilage matrix, and osteoblasts replace the cartilage
scaffold by bone. Eventually, the osteoarthritic joint assumes a bone-on-bone condition.
Hypertrophic chondrocytes synthesized uncarboxylated Matrix Gla Proteins which loses the ability to bind calcium
and are unable to prevent unwanted calcification leading to the development of bone spur formation, a common
complication of late-stage osteoarthritis.
