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Osteoarthritis 1: physiology, risk factors and causes of pain

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The first in a three-part series on osteoarthritis explores the complex pathophysiology of the condition, its diagnosis and how it causes pain


Osteoarthritis (OA) is a synovial joint disorder characterised by pain, stiffness, and restricted function. It is often classed as a degenerative disease because the affected joints deteriorate over time. This article, the first in a three-part series, describes the complex pathophysiology and causes of pain in OA, risk factors, and how it is diagnosed.

Citation: Swift A (2012) Osteoarthritis 1: physiology, risk factors and causes of pain. Nursing Times [online]; 108: 7, 12-15.

Author: Amelia Swift is a lecturer in nursing at the University of Birmingham.


Osteoarthritis (OA) is a synovial joint disorder involving cartilage, bone and synovial membrane. Onset and progress of the condition is usually slow; symptoms of pain, stiffness and restricted function usually emerge in people aged over 40, and prevalence rises with increasing age.

It is difficult to specify prevalence of OA because of the different joints involved. It can affect both small joints, such as those in the thumb, toes and fingers, and the large load-bearing joints of the hip and knee.

Prevalence varies between populations due to factors such as genetics and environment. Dagenais et al (2009), who carried out a review of studies providing data about the prevalence of hip OA, found it affects between 0.9% and 27% of the population. Evidence suggests the rates of knee OA are between 17% and 47% (Horvath et al, 2010; Salve et al, 2010)

OA is often classed as a degenerative disease because the affected joints deteriorate over time. It is also commonly known as a non-inflammatory condition where pain is generated by movement of the diseased joint even though inflammation is a symptom (see below).

Diagnosis of OA

OA can be diagnosed from a persistent history of pain, stiffness and loss of function, and from risk factors. X-ray is the gold standard for diagnosis. OA is diagnosed and graded by severity by the degree of bony changes seen on an X-ray. The most commonly used X-ray tool is the Kellgren-Lawrence scale. This ranges from a score of zero, where no change is seen, to a maximum score of four. A maximum score means the changes are severe, with significant joint space narrowing, bony changes at the joint margins and alteration in the subchondral bone. A number of X-ray views may be needed to diagnose OA, especially in the knee joint.

Pathophysiology and risk factors

OA involves the loss of articular cartilage, the formation of bony spurs at the joint margin (osteophytes), inflammation of the synovial membrane and changes to the subchondral bone. The chronology of alterations in the bone, synovium and cartilage depends on the triggers for OA; changes in each tissue affect surrounding tissues. The pathophysiology of OA is complex as it comes in subtypes including:

  • Inflammatory, to a varying extent;
  • Nociceptive (tissue damage) pain;
  • Pain at rest, which can have the same characteristics as neuropathic pain.


The bone just beneath the cartilage in the synovial joint is known as subchondral bone, and has a number of different zones.

The uppermost zone, the subchondral bone plate, is composed of relatively non-porous bone with a limited blood supply. Beneath this is a spongier layer of bone called cancellous or trabecular bone.

In a healthy person, bone is constantly modified by modelling and resorption. This allows it to repair and adapt to changing mechanical requirements.

In some people, the composition or properties of bone are affected by inherited disorders, such as Stickler syndrome, which can lead to a much earlier onset of OA. In most people, the bone changes in OA are seen much later in life, and the triggers are poorly understood.

The subchondral bone plate thickens, the character of the trabecular bone changes, new bone is formed at the
joint margins (osteophytes) and subchondral cysts form. These changes are defining features of OA (Goldring and Goldring, 2010).


Cartilage is a relatively vulnerable tissue, and a number of factors, such as age, predispose it to damage.

Pressure (loading) on cartilage causes the cartilage cells (chondrocytes) to produce a collagen and protein matrix. Replacement process of the matrix is normally a slow process, but excessive loading can lead to activation of enzymes (metalloproteases) that digest it, leading to thinning and damage (Goldring and Goldring, 2007). Modifiable factors that contribute to abnormal or excessive loading of the cartilage include:

  • Obesity;
  • High-level, high-impact sport or occupational activities;
  • Repetitive and long-term occupational factors, such as repeated kneeling, twisting and handling heavy weights while standing (Ratzlaff et al, 2011; Yoshimura et al, 2004).

Non-modifiable factors include:

  • Being female;
  • Congenital joint abnormalities;
  • Genetic polymorphisms;
  • Ethnicity with susceptibility in particular joints varying between ethnic groups;
  • Ageing (Loughlin, 2011; Allen, 2010; Gandhi et al, 2010; Messier, 2008; Verzijl et al, 2002).

Interaction between these factors can make it difficult to know the exact contribution of each. OA is more likely in those who are female, obese, have metabolic syndrome, manual jobs that involve kneeling, twisting and carrying, and are from ethnic and/or socioeconomic backgrounds that carry an increased incidence of any of these factors.


Once cartilage has been damaged, the products of that damage are engulfed and digested by synovial cells. This leads to the production of inflammatory mediators, such as pro-inflammatory cytokines interleukin IL-1, IL-6 and IL-8, tumour necrosis factor and prostaglandin PGE2. Cartilage damage triggers synovial inflammation, which in turn adds to cartilage damage (Pearle et al, 2007). Low-level (subclinical) synovial inflammation is present in most people with OA and many, even those with no synovial inflammation, will experience intermittent inflammatory flare-ups (Bonnet and Walsh, 2005).

The degree of inflammation is a key difference between OA and rheumatoid arthritis. OA is not always recognised as an inflammatory disease because there are often low levels of leucocytes in the synovial fluid, one of the parameters used to identify an inflammatory condition. Inflammation in OA is usually restricted to a specific area of a joint, but can sometimes be so pronounced that inflammatory chemicals are seen in the circulation as well as the synovial fluid. The degree of inflammation is associated with disease severity and pain. It is likely there are a number of subtypes of OA, some causing a much higher level of synovitis and inflammation than others (Pearle et al, 2007).

Causes of pain in OA

Pain is transmitted from peripheral tissues to the dorsal horn of the spinal cord, and from there to the brain along sensory nerve fibres. The main type of nerve fibre involved in transmission of OA pain is the small unmyelinated slow C-fibre. This carries signals relating to dull and aching pain sensations. There are also A-beta fibres in the joint that transmit information about touch, and A-delta fibres that are responsible for the detection and transmission of signals from pin-prick and heat.

Sensory nerves that travels from the periphery to the spinal cord are called the primary afferent fibres. These connect with nerve fibres in the dorsal horn, carrying pain or touch signals to the brain stem. These dorsal horn nerve fibres are called projection neurons; there are two main types of these:

  • Pain-specific projection neurons that only transmit pain, no matter what incoming signal activates them. These are also known as nociceptive specific neurons, and reside mainly in the superficial layers of the dorsal horn;
  • Wide dynamic range (WDR) cells, a group of projection neurons that can differentiate between pain signals and touch signals, and can also code the signal’s intensity and location.

Chemical mediators

The process of inflammation in the OA joint leads to the production of a number of chemical mediators. These sensitise the sensory nerve endings (peripheral sensitisation), lowering their threshold and creating the right conditions for other chemical mediators to create an action potential. These include the following:

  • Substance P;
  • Adenosine triphosphate;
  • Nitric oxide;
  • Prostaglandins;
  • Cytokines, such as interleukin-6.

The part of the nerve that senses these chemicals is called the nociceptor (the sensory organ of pain). Nociceptors are located throughout the whole joint in the capsule, the ligaments, the menisci and the bone. There are no nociceptors in cartilage.

The frequency of action potentials reaching the dorsal horn via the primary afferent fibre determines the response of the spinal cord cells to the pain signal. When a person is experiencing a lot of pain, the frequency of signals reaching the dorsal horn is high. This causes the primary afferent fibre to release the neurotransmitters glutamate, substance P and calcitonin-gene related peptide.


Neurotransmitters have target receptors on the projection neurons, whose role is to conduct the pain signal from the spinal cord to the brain stem. The more neurotransmitters released by the incoming primary afferent fibre, the more likely it is the projection neuron will achieve its threshold to generate an action potential and send the signal to the brain. The key neurotransmitters involved in transmission of pain across the first synapse in the dorsal horn are glutamate and substance P.

The projection neuron communicates the pain signals to the brain stem and from there to the cortex. Connections between a number of centres in the brain integrate pain with other influencing factors, such as depression, anxiety and lack of sleep. The brain stem sends signals back to the spinal cord, which can either facilitate or inhibit pain signalling. The main neurotransmitters involved in this process are:

  • Norepinephrine (noradrenalin);
  • 5-hydroxytryptamine (5-HT or serotonin);
  • Encephalin.

Once these neurotransmitters are released into the dorsal horn, they act directly on primary afferent fibres and projection neurons. This leads to the release of the chemical mediators responsible for the inhibition of the primary afferent or projection neuron. The two neuromodulators involved in pain inhibition are gamma-aminobutyric acid and glycine.

Central sensitisation

When the pain signals reaching the dorsal horn are intense or prolonged, they set up an internal amplification system.

This process is called central sensitisation, which improves the protection afforded to the joint by the experience of pain. Because the process increases the sensation of peripheral pain, patients will be more inclined to rest to avoid further pain and protect the area.

One of the chemical mediators of this process is prostaglandin. This is produced by the projection neuron, and is diffused back to the primary afferent nerve, where it causes an increased release of glutamate and substance P.

Prostaglandin also acts on the projection neuron itself, turning off the glycine receptor, one of the inhibitory neurotransmitters. Glycine is needed to stop mechanoreceptor A-beta fibres causing the nociceptive-specific projection neurons to fire.

Usually, A-beta fibres do not cause the nociceptive-specific projection neuron to fire because of this glycine block. However, once the block is removed by prostaglandin, the A-beta fibre signals lead to firing of the nociceptive-specific projection neuron.

Unlike the WDR cell, this neuron cannot distinguish between pain and touch, so any input of sufficient intensity leads to a pain signal being fired off to the brain. This is why touch can sometimes cause pain. Pain caused by innocuous (non-harmful) touch is called allodynia.

Once the pain stimulus is removed or its intensity diminishes, central sensitisation stops and the dorsal horn stops amplifying pain signals.

Central sensitisation can become pathological – it stops having a purpose and becomes disproportionate to the nociceptive input. Very little or no painful stimulus is required to evoke pain in some cases.

This sort of central sensitisation was first described in connection with pain related to neuropathic pain. It is now known to be important in OA pain.

Central sensitisation can help to explain why the amount of joint damage and inflammation does not always correlate with the amount of pain experienced. It also explains why people with OA feel pain in response to touch.


OA is a painful disease of the synovial joints. It usually starts in people aged 40 and over, and increases in prevalence with age.

Factors that increase the risk of OA include being overweight and having metabolic syndrome. Participating in a lot of heavy lifting, twisting and kneeling, and high-level impact sports can also increase the likelihood of OA developing. There also appear to be genetic influences, which help to explain why certain ethnic groups have a higher prevalence of OA than others.

Research has helped understanding of the pathophysiology of OA, and the pain it causes. OA affects all the joint tissues, and the changes in those tissues cause inflammation that can vary in intensity.

OA pain is caused by inflammatory mediators, which can lead to central sensitisation of the pain processing cells in the dorsal horn of the spinal cord. Central sensitisation means pain signals are amplified in the dorsal horn, and projection neurons become far more sensitive to pain and touch signals. People with OA may therefore have pain that is disproportionate to the damage of the joint seen on X-ray. 

Box 2. Key terms

  • Action potential: an-all-or nothing response to the influx of sodium or calcium ions into a neuron, which leads to an electrical signal being transmitted along the axon of the nerve
  • Activation threshold: the minimum difference in electrical charge between the cell and its surroundings that will lead to the generation of an action potential
  • Cartilage: a flexible tissue composed of a network of collagen, trapping large proteins within it. Cartilage is produced by cartilage cells called chondrocytes. Articular (or hyaline) cartilage covers articulating bone surfaces.
  • Chemical mediator: a molecule or compound produced that initiates a chemical reaction when it combines with another substance or a receptor
  • Neurotransmitter: a chemical signal that transmits a message from one neuron to a target cell across a synapse (for example glutamate).
  • Nociceptor: a sensory nerve receptor that responds to damaging or potentially damaging stimulation (chemical, thermal or mechanical)
  • Prevalence: the total number of cases in a given population at a specific time
  • Primary afferent fibre: the afferent (incoming) sensory nerve fibre as it enters the dorsal horn
  • Projection neuron: the secondary neuron that receives signals from the primary afferent fibre and conducts them to the brain stem
  • Receptor: a molecule (usually on the surface of a cell) that responds to a chemical signal (for example prostaglandin or substance P)
  • Sensitisation: a process involving chemical mediators and neurotransmitters that leads to a decrease in the activation threshold of a nerve (makes it more sensitive or responsive to stimuli)
  • Synovium: also known as the synovial membrane. It is a layer of tissues a few cells thick that lines the joint and the tendon sheath. It protects the joint by acting as a selective barrier and produces lubrication for the joint
  • Subchondral bone: the layer of bone just below the cartilage

Key points

  • Osteoarthritis (OA) is a synovial joint disorder involving cartilage, bone and the synovial membrane. It can affect small and large joints
  • OA can be diagnosed from a persistent history of pain, stiffness and loss of function. X-ray is the gold standard
  • Risk factors include: age, being female; obesity; metabolic syndrome; repeated kneeling or twisting; or handling heavy weights
  • OA pain is caused by inflammatory mediators, which lead to central sensitisation of the pain processing cells in the dorsal horn of the spinal cord
  • Hip OA affects between 0.9% and 27% of the population, and the rates of knee OA are between 17% and 47%
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