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Written by: Dr Jeremy Steinberg – created: 15 August 2021; last modified: 25 June 2022

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Osteoarthritis is a degenerative joint disease that is characterised by cartilage loss, subchondral bone remodelling, and osteophytosis. Clinically there may be variable reduced range of motion, swelling, and joint pain.

Aetiology and Risk Factors

There is no single distinct aetiology. Rather there are a variety of risk factors.

  • Developmental: This includes abnormal biomechanics (such as valgus and varus knee alignment), and abnormal joint morphology (such as hip dysplasia, slipped epiphysis, Perthes)
  • Previous diseases: any diseases that effect synovial joints such as rheumatoid arthritis and gout, which can alter the shape of the joint and predispose to the development of secondary osteoarthritis
  • Trauma: for example fracture of a shaft leading to a joint resulting in abnormal forces on the joint, and fracture of a joint itself altering its shape altering the mechanical loading. Trauma also includes surgical intervention such as meniscectomy which predisposes to osteoarthritis
  • Other insults leading to abnormal forces or direction or forces: obesity (some joints but not others), and conjecturally excessive moments (muscular forces that exert on the joint) and excessive shear forces
  • Genetic predisposition. There is important explicit evidence in lumbar disc degeneration through the studies of twins. Biomechanical factors in this setting only account for some of the variance, while larger proportions are due to genetic factors.[1] These genetic factors confer a predisposition but do not in themselves guarantee the development of degenerative changes.
  • Increasing age
Abnormal force and abnormal shape risk factors
Abnormal Force Direction Abnormal Joint Shape
Insults Obesity, and conjecturally excessive moments and excessive shear forces
Trauma Shaft fracture Joint fracture
Previous Disease Rheumatoid arthritis, gout, etc
Developmental Valgus and varus knee alignment Hip dysplasia, slipped epiphysis, erthes


The pathophysiology of osteoarthritis is often described as "wear and tear." A more accurate statement is "tear, flare, and repair" because joints are metabolically active structures and not simply mechanical structures. The term tear reflects factors such as obesity, overuse, and malalignment. Flare represents inflammation. The repair process can lead to a symptom free but structurally altered joint, or can be suboptimal with a mismatch between repair and degradation resulting in persistent pain and disability.

Extracellular Matrix Components

Main article: Fibrous Connective Tissues

The extracellular matrix of cartilage is made up of two main macromolecules: type II collagen and aggrecan. Aggrecan is a large aggregating proteoglycan which retains water. The type II collagen provides intrinsic resistance to tension, and allows the proteoglycans to swell against it to provide resistance to compression. There are other more minor components that also play a role in matrix structure such as other forms of collagen (e.g. types IX, XI, and VI collagen), proteoglycans (e.g. biglycan, decorin), and cartilage oligomerix matrix protein.

Matrix Synthesis and Degradation

See also: Synovial Joints

In the normal state there is an equilibrium between synthesis and degradation of the extracellular matrix. Synthesis refers to the production of the collagens and proteoglycans, and this process is stimulated by a variety of factors such as IGF, TGF, and FGF.

In osteoarthritis there is a change in the ratio of the KS/CS ratio with a preference for keratan sulphate which has only one compared to two negative charge sites and so has less ability to retain water.

Degradation refers to the production of a variety of MMPs and ADAMTs proteinases whose function is to degrade the matrix. Degradation allows for clearing of old components so that fresh components can be synthesised. The degradative process is controlled by the TIMP compounds. The chondrocyte is continuously metabolically active with continuous synthetic and degradative processes.

The classic degradative enzymes, produced in the chondrocyte and synovium, are the metalloproteinases (MMPs) which facilitate the turnover of the extracellular matrix in both normal and osteoarthritic states. It is thought that MMP-1 is the primary collagenase in rheumatoid arthritis, and MMP-13 is the primary collagenase in osteoarthritis. The role of MMP-1 may be distinct in each joint, being elevated in knee osteoarthritis, and reduced in hip osteoarthritis. MMP-3 on the other hand is reduced in osteoarthritis, and elevated in rheumatoid arthritis. There are various other changes in MMP expression in osteoarthritis.[2]

The A Disintegrin And Metalloproteinase with Thrombospondin Motifs (ADAMTS) group of proteinases were discovered later and are involved in both the synthesis and degradation of the extracellular matrix. ADAMTS enzymes include the procollagen propeptidases (ADAMTS-2, -3, and -14) that are involved in collagen biosynthesis, and the aggrecanases (ADAMTS-1, -4, -5, -9, and -15) that are involved in aggrecan degradation. There are various changes seen in osteoarthritis with the expression and activity of these proteinases.[3] ADAMS-4 and -5 are key proteinases active in early OA. They act to cleave the interglobular region between G1 and G2, leaving a shortened aggrecan with fewer fixed charges.

In the arthritides there is a disruption of this balance so that the degradative processes are favoured with elevated levels of active proteinases leading to the destruction of collagen and aggrecans in the cartilage. In osteoarthritis it is the proteinases that are produced by chondrocytes that play a major role. While in the highly inflamed rheumatoid joint, it is the chondrocytes, synovial cells, and inflammatory cells that all contribute to degradation.

There is initially a gradual loss of proteoglycans, and this results in the collagen of the matrix being exposed. After exposure of the collagen fibres, these can be acted on by proteinases.

There are also important inhibitors, and the tissue inhibitors of metalloproteinases (TIMPs) are able to inhibit the activity of MMPs and potentially ADAMTS. In osteoarthritis there can be an imbalance between metalloproteinase and TIMP activities[2]

Cartilage oligomerix protein (COMP) is also known as thrombospondin 5. It's exact function remains unclear but it appears to be an important regulator of extracellular matrix assembly and stabilisation of the matrix through interacting between collagen fibrils and matrix components. It appears to be a marker of cartilage turnover and has been studied as both a diagnostic and prognostic indicator of osteoarthritis.[4]

Synovial Membrane and Fluid

The degradative products of proteoglycans and collagens are found in the synovial fluid and contribute to the debris characteristic of an osteoarthritic joint. Leftover proteinases are also found in the synovial fluid.

The debris causes a reaction in the synovial membrane. There may be hyperplasia of the tissue with the formation of villi, and there may be inflammatory episodes which can cause overt synovitis. Inflammation can eventually lead to fibrosis of the synovial membrane and the joint capsule which can cause clinical stiffness.

Degradative enzymes can be stimulated by various inflammatory mediators such as interleukin-1 and TNF-alpha. These enzymes can also suppress the synthetic arm of matrix homeostasis, and this is their main function.


As there is a decrease in the matrix, there is reaction at the joint margins in the form of osteophytosis. Blood vessels grow into the sides of the joints to furnish this new bone. Osteophyte development can be viewed as an attempt to improve the efficiency of the joint. This is because of an increase in the surface are of the joint, leading to a reduction in the force per unit area. An analogy is walking on snow with snow shoes versus high heels.

Hyaluronan Cysts

These are cysts not bone growths on the edges of the weakened cartilage.


In viewing changes in the expression of various genes, it is important to remember that such changes don't necessarily mean that a particular enzyme is causative in the pathogenesis of osteoarthritis. There may be different factors involved across the spectrum of osteoarthritis from mild to end-stage.[3]


Main article: Cartilage Biomechanics

Synovial joints are supported by fluid pressure and solid matrix in a 20 to 1 ratio. With the above pathological processes there is a change in the biomechanics of the osteoarthritic joint.

In early osteoarthritic change, there is increased water content and decreased proteoglycan content. This leads to increased tissue permeability, which in turn reduces the fluid pressurisation mechanism of load support in cartilage. In this setting, the solid matrix is called upon to bear more of the load, which is detrimental to the long term viability of cartilage. The disordered matrix is weaker and is less able to take on load.

End-stage Changes

Macroscopically, initial changes are fibrillation which are small cracks. These then progress to larger cracks and eventually cartilage erosion. Ultimately the underlying bone is exposed. At this point the bone attracts a hyperaemia undergoes sclerosis. The hyperaemia may be a cause of intraosseous venous hypertension.

As the exposed bone is exposed to forces it experiences eburnation (polishing due to rubbing, which may underlie the clinical feature of crepitus through vibration), the formation of subchondral bone cysts, and with sufficient forces it may undergo necrosis. Bone is poorly designed to experience intermittent compressive loads, it is more suited to static loads and it needs the cartilage for protection.

Relationship to Pain

One hypothesis of how an osteoarthritic joint may be painful is the theory of intraosseous venous hypertension. Because of the hyperaemia, the veins in the subchondral bone are distended and the pain results in increased tension in the adventitia of those veins.

In the spine, zygapophyseal joints can be a source of pain, but there is no correlation between radiological osteoarthritis and pain. Osteoarthritis is more common with age regardless of pain.

In the lumbar spine. there is no difference in the grade of arthropathy between painful and non-painful zygapophyseal joints as determined by controlled intra-articular blocks. Similarly there is a clinically insignificant correlation between back pain and lumbar degenerative disc changes, with such changes not being related to pain the majority of the time.[5]


A working diagnosis of pain can be made without an x-ray if:

  1. Age 45 years or over.
  2. Chronic (lasting 3 months or more) joint pain that is worse with use.
  3. Morning stiffness lasting no more than half an hour.
  4. Alternative diagnosis is unlikely.


Despite the rapid improvement of treatment options and strategies for inflammatory arthritis there remain very limited effective options for treating osteoarthritis.



Corticosteroid injections can be effective in the short but not long term. A 2009 systematic review found evidence for significant relief at one week.[6]

There is some concern about chondrotoxicity of corticosteroids. A 2017 RCT compared intra-articular triamcinolone versus saline injected every three months for 24 months in patients with symptomatic knee osteoarthritis. At 24 months they found a significant loss of cartilage in the treatment group (MRI cartilage thickness change of -0.21 vs -0.10 mm) with no significant difference in knee pain (-1.2 vs -1.9).[7]

Hyaluronic Acid

This is not commonly used in New Zealand due to lack of funding and lack of evidence of clinically significant efficacy over placebo. The most generous trials indicate that there is a small but clinically meaningless benefit over placebo.

Platelet Rich Plasma

Another controversial treatment option with mixed trial results.



See the following open access "Year in Review" series published by Osteoarthritis and Cartilage:


  1. Battié MC, Videman T, Kaprio J, Gibbons LE, Gill K, Manninen H, Saarela J, Peltonen L. The Twin Spine Study: contributions to a changing view of disc degeneration. Spine J. 2009 Jan-Feb;9(1):47-59. doi: 10.1016/j.spinee.2008.11.011. PMID: 19111259.
  2. 2.0 2.1 Kevorkian L, Young DA, Darrah C, Donell ST, Shepstone L, Porter S, Brockbank SM, Edwards DR, Parker AE, Clark IM. Expression profiling of metalloproteinases and their inhibitors in cartilage. Arthritis Rheum. 2004 Jan;50(1):131-41. doi: 10.1002/art.11433. PMID: 14730609.
  3. 3.0 3.1 Yang, C-Y et al. “ADAMTS and ADAM metalloproteinases in osteoarthritis - looking beyond the 'usual suspects'.” Osteoarthritis and cartilage vol. 25,7 (2017): 1000-1009. doi:10.1016/j.joca.2017.02.791
  4. Tseng, Susan et al. “Cartilage Oligomeric Matrix Protein (COMP): A Biomarker of Arthritis.” Biomarker insights vol. 4 33-44. 17 Feb. 2009, doi:10.4137/bmi.s645
  5. Bogduk N. Degenerative joint disease of the spine. Radiol Clin North Am. 2012 Jul;50(4):613-28. doi: 10.1016/j.rcl.2012.04.012. PMID: 22643388.
  6. Hepper, C. Tate; Halvorson, Jason J.; Duncan, Stephen T.; Gregory, Andrew J. M.; Dunn, Warren R.; Spindler, Kurt P. (2009-10). "The efficacy and duration of intra-articular corticosteroid injection for knee osteoarthritis: a systematic review of level I studies". The Journal of the American Academy of Orthopaedic Surgeons. 17 (10): 638–646. doi:10.5435/00124635-200910000-00006. ISSN 1067-151X. PMID 19794221. Check date values in: |date= (help)
  7. McAlindon, Timothy E.; LaValley, Michael P.; Harvey, William F.; Price, Lori Lyn; Driban, Jeffrey B.; Zhang, Ming; Ward, Robert J. (2017-05-16). "Effect of Intra-articular Triamcinolone vs Saline on Knee Cartilage Volume and Pain in Patients With Knee Osteoarthritis: A Randomized Clinical Trial". JAMA. 317 (19): 1967–1975. doi:10.1001/jama.2017.5283. ISSN 1538-3598. PMC 5815012. PMID 28510679.

Literature Review