Arthritis. Part 1. Not wear and tear.

What is Osteoarthritis, and what causes it?

The first section of this post is in ‘plain English’, with the full referenced version below designed for health professionals.


Plain language version.


Osteoarthritis (OA) is a common joint complaint, most commonly affecting the hips, knees, wrist and hands. OA is so prevalent in the elderly that it is often considered a normal part of aging - like the loss of muscle strength, and wrinkling of skin that we consider normal with aging too. However for some people, OA can develop well before old age, and conversely some people get will in to their 80’s with few symptoms. Just as lifting weights can maintain muscle mass as we age, and avoiding certain things like smoking, and excess sun exposure can minimise skin wrinkling, certain variables can impact upon the development of OA. So although OA is often thought of as just ‘wear and tear’ of the joint surfaces, I hope to show you in these series of posts, how that is not correct.


OA is diagnosed by a combination of X-ray or MRI findings, and the presence of a specific symptom profile. The MRI or X-ray findings characteristic of OA show changes to the cartilage and bone. The cartilage thins, hardens, and becomes less lubricated; the bone can accumilate fluid, form micro-fractures, and develop ‘Osteophytes’ - extra bone growth around the joint. It is these Osteophytes that cause the nobbly appearance around arthritic knees, toes, and fingers.


The symptom profile characteristic of OA - pain and stiffness around a joint that is worse in the morning, eases with gentle movement, but is aggravated with high exertion - must also be present for a definitive, clinical diagnosis of ‘Osteoarthritis’. Interestingly, studies have shown that between 20%-60% of people the aforementioned findings on X-ray or MRI have no symptoms. When there is some evidence of these types of changes to the joint, that don’t fully qualify as ‘Osteoarthritis’, they are usually referred to a ‘arthritic changes’.


It can be useful to imagine these changes on a spectrum, from the healthy, ‘normal’ joints of a 20 year old, to heavily arthritic joints, that are candidates for joint replacement. Symptoms do correlate with the severity of these changes - as they develop, people are more likely to have symptoms - but there is not a direct cause and effect between joint changes and pain. This is, in part, due to the fact that it is not just the ‘hard’ parts of a the joints that are affected. The ‘soft’ connective tissue- tendons, ligaments, muscles, and even the fluids around the joint can be affected by OA. These soft tissues, and to an extent the health of the harder tissues are amenable to change and improvement.


OA has traditionally been differentiated from similar conditions, such as rheumatoid arthritis (RA), by being referred to as ‘non-inflammatory arthritis’. RA is an autoimmune disease, where impaired regulation of the immune system causes it to ‘attack’ the bodies own tissue - an inflammatory reaction. RA requires  a systemic management plan, usually with involving medication. Despite this classic distinction there is growing evidence that inflammation is in fact crucially involved in the development of OA, both locally to the joint as a result of trauma and repeated microtrauma, and systemically as the function of general health.


One of the biggest risk factors for OA is obesity. People with a Body Mass Index (BMI) over 30 have a 6.8 times higher risk of developing OA of the knee. We used to think that this was the result of increased forces through the joint. However, studies have found in fact people with a high body mass but low body-fat mass (heavy with muscle, not with fat) are actually at a lower risk of developing OA. It’s also been shown that having a high body-fat mass, regardless of activity levels (regardless of joint use), is associated with developing OA. In fact, being overweight increases the risk of developing OA in non-weight bearing joints - obese people have more arthritis in their thumbs, than do non-obese people!


We now know that fat tissue (technically known as ‘adipose tissue’) actually produces a number of chemicals that regulate the function of the body. When people have an excess of adipose tissue, we also have an excess of these chemicals released into the blood. These chemicals create what is sometimes referred to as a ‘proinflammatory state’ - meaning they tip the balance in the body towards inflammation. This proinflammatory state disrupts the balanced, normal functioning of tissue, causing a cascade of changes that increase the risk of OA (and many many other conditions).


This ‘balanced, normal functioning of tissues’, is a process, known technically as homeostasis. Disruption to homeostasis usually results in some form of disease. So: Obesity disrupts homeostasis of the joints, by producing too much of certain chemicals circulating in the blood, altering the function of cells multiple different tissues around joints.


As well as obesity, another factor that can disrupt the homeostasis of the joints is disrupted sleep! It may seem hard to imagine how poor sleep can lead to OA, but some interesting research recently discovered a ‘switch’ within the cells of the cartilage that are switched on with sleep. When this switch is turned on the cells carry out their normal maintenance of the cartilage, keeping the joint healthy. Chronicley disrupted sleep (when sleep in poor, repeatedly, over a long period of time) impairs this homeostatic mechanism, and leads to increased rates of OA due to an impairment of the bodies repair mechanisms.


We do not know all the mechanisms that can disrupt the body’s homeostatic mechanisms, but it’s safe to assume that the same things that affect our general health will also have an impact upon our joints. Eating healthy, having a healthy body weight, doing exercise, getting enough sleep, are all associated with lower risk of almost every known disease, and arthritis is no different. Just another reason to form good habits.


Here we have explored some of the ways in which general health is associated with Osteoarthritis, and hopefully begun to dispel the myth that arthritis is simply ‘wear and tear’ - indeed it is more accurate to describe it as ‘wear and disrepair’. In the next post in this series, we will look at the role of mechanical forces and exercise in the development, prevention, and management of OA.

Below is the full version

For professionals.

Osteoarthritis (OA) is a common, painful complaint affecting synovial joints. Most commonly the knees, hips, and the wrist and hands. The ubiquity of OA in the elderly means that it is commonly considered a normal part of aging; akin loss of strength and wrinkling skin. However, the age of onset, rate of progression, and severity at which these symptoms develop can differ hugely between individuals, and even between joints within an individual. Just like with age-related strength loss, and skin wrinkling, various environmental and lifestyle factors can also impact how OA develops.


So what actually is OA? What are the tissue specific changes, and associated functional changes that we can identify as being arthritis? And what are the causative factors, and risk factors for developing this complaint?


OA, primarily but not exclusively, affects the articular surfaces of joints and subchondral bone. Radiographically it is identified by the presence of, in variable degrees: joint narrowing; subchondral sclerosis and cyst formation; and the formation of osteophytes, and calcification of chondral surfaces (Scott, et al 1993). The classic symptoms of OA are joint pain and stiffness, especially first thing in the morning. Symptoms tend to follow a reverse bell curve pattern in response to activity, with easy movement easing symptoms, and more strenuous exercise aggravating symptoms - however, what constitutes strenuous is relative to each person's ability, and is therefore amenable to improvement.


There is a poor correlation between detectable tissue pathology and symptoms - although there are coherent subjective, clinical and radiographic findings that can be described as ‘Osteoarthritis’, only 40%-80% of people with evidence of OA from radiographic studies have symptoms  (Basija, et al. 2010). That is to say: although everyone with symptomatic OA, by definition, has radiographic evidence of changes to the joint, the reverse is not true. It could be useful to think of Osteoarthritic pathogenesis as being on a scale, ranging from mild objective signs (radiographically measured), to severe objective signs, with symptoms being correlated, but not constrained by these objective measures.



Osteoarthritis is a disease of the joint as a whole, with wide ranging effects upon: subchondral bone; the synovium; ligaments and menisci; the joint capsule; subchondral sclerosis; as well as chondral thinning, cysts, and microfractures; and synovitis (Robinson et al, 2016, Pessler, et al. 2008, Ishijima, et al. 2011). The pathological process underlying these changes involves a homeostatic imbalance between anabolic, and catabolic processes, involving: hypertrophy and death of chondrocytes; immune activation and infiltration; chondrocyte hyperplasia and autophagy, osteoclast mediated bone remodelling (Loeser, et al. 2012); and the production of matrix metalloproteinases (MMP’s) (Goldring, Marcu 2009).  MMPs are enzymes that degrade chondral proteins such as aggrecan - a key proteoglycan component of cartilage (Burrage. 2006, Goldring, Marcu 2009). Each of these changes affects the structure or function of the joint, altering its mechanical properties.


Angiogenesis - from the subchondral bone into the otherwise avascular articular cartilage is another critical feature of Osteoarthritis. This neovascularisation results in: a loss of cartilage thickness and mechanical properties, further affecting function; and the presence of free nerve ending in otherwise anaesthetic weight-bearing structures such as the hyaline cartilage (Wang, et al. 2017, Robinson, et al. 2016).


Synovitis is an integral part of the disease process of Osteoarthritis - normally manifesting prior to cartilaginous degeneration, or structural changes. Clinical signs of synovitis include: effusion; joint swelling; palpable tenderness; sudden increases in pain; night pain; and morning stiffness (Mathiessen, Conaghan. 2017). In addition to its parenchymal role in diarthrodial joints, synovial tissue also surrounds tendons, and is integral to the structure  and function of bursae and fat pads.


The synovium contains micro-vascular, lymphatic, and nerve tissues. The innermost layer of the synovium - the intima - in normal tissue is just 1-4 cells thick with a collagen scaffold. These cells are primarily macrophage-type cells, and fibroblast-type cells. Most of the fibroblasts are specially adapted to the production of hyaluronan and lubrican components of synovial fluid - essential for its lubricant function. Macrophage-type cells conversely are involved in catabolic, and immune regulation and function, including the production of pro-inflammatory cytokines and MMP’s (Smith. 2011, Bondeson, et al. 2006). It appears that the same disease processes that leads to synovial dysfunction within the joint also affects the synovium of tendons, bursae and fat pads (de Vos. et al. 2016). This in part explains the whole-joint, or even whole-person presentation of Osteoarthritis.


As well as having an effect up tissue function, these inflamed tissues also cause much of the symptomatic pain and stiffness associated with OA, via sensitisation of nerve endings. It is not a stretch to imagine how the same disease process affecting the synovium could also alter the function of the macrophage-like cells, and fibroblasts of the perimysium, contributing towards to the characteristic myo-fascial presentations of more progressed Osteoarthritis.


So what are the factors that precipitate the full range of tissue changes seen in Osteoarthritis?


As all tissues go through catabolic/anabolic, and repair/remodelling cycles on a daily rate. Poor sleep can impair these process by disrupting the normal circadian rhythm and altered gene expression as a result. Chronic sleep disruption of mice predisposes these animals to to OA-like damage, which has linked to the action of a single gene ‘BMAL1’ - a gene mice share with humans. Cartilage of people with OA show disrupted transcription factors from this gene (Dudek, et al. 2015). Clearly not all people with OA suffer from disrupted circadian rhythms - but this clear, isolated epigenetic change is just a single example of how homeostatic impairment can have significant effect upon body function and even composition.


Rheumatoid Arthritis is a systemic autoimmune disease - fundamentally, a dysregulation of the immune system that manifests, amongst other complaints, as joint inflammation, and pain and stiffness. In the normal synovium, fibroblast greatly outnumber macrophages, but this shifts in RA, with macrophages accounting for as much as 80% of the intimal cell population (Smith. 2011).


Although Osteoarthritis has long been described as ‘non inflammatory’, increasing evidence suggests that in-fact low-grade systemic inflammation to be a principal factor in the development of the disease (Sokolove, Lepus. 2013. Robinson, et al. 2016).  It is thought that the inflammation associated with OA affects the joints via dysregulation of the Damage Associated Molecular Patterns (DAMPs) mechanism - a function of the innate immune system; and via the Complement-system - ultimately disrupting the normal repair and regulatory functions of the cartilage and synovium, and increase the presence of prostaglandins and leukotrienes in the cartilage and synovium - initiating a cascade of catabolic, and impaired repair processes (Robinson, et al. 2016, Loeser, et al. 2012, Smith. 2011, Bondeson, et al. 2006). There is a proportional association between OA symptoms, synovitis and elevated levels of serum C-reactive protein, with the later being predictive of the development and progression of OA (Pelletier, et al. 2001), however the serum inflammatory markers seen in OA are only moderately increase compared with Rheumatoid Arthritis, and the local inflammation see within the joints has a very different character (Robinson, et al. 2016).


Interestingly these same inflammatory markers associated the the development of OA, are also produced locally to the joint following tissue injury, within joints (Robinson, et al. 2016), fitting with the finding that arthritis is more common in joints with a history of previous injury (Chaganti, Lane. 2011).


People with a BMI over 30 were 6.8 times more likely to suffer OA of the knee (Coggon, et al. 2001). There is also emerging evidence of a role of elevated blood glucose level in Diabetes being a risk for OA, independent of Obesity (Dubey, et al. 2018). Obesity can affect joints via excessive joint loads and altered mechanics, but also via hormonal and cytokine dysregulation - in-fact Obesity also increases rates of OA in non-weight bearing joints (King. et al. 2013). Obesity leads to a systemic, low-grade inflammatory state involving an increase in circulating cytokines produced by adipose tissue - ‘adipokines’-  such as Leptin, that affects the ability of chondrocytes to respond to mechanical loading, and to repair after microtrauma (King. et al. 2013, Ouchi, et al 2011). Adipose tissue also produces circulatory IL-6 and TNF, and a number of other proinflammatory agents - and unsurprisingly an excess of adiposity is linked to elevated levels of these cytokines, as well as increased levels of circulating C-reactive protein (Hotamisligil, et al. 1993, Ouchi, et al. 2011, Beavers, et al. 2015) This proinflammatory state, as identified in previous paragraphs, is thought to be involved in the dysregulation of the synovium and chondral tissue, and the initiation of Osteoarthritis.


Wang. et al (2007) found that individuals with a higher fat-free mass had a greater degrees of normal cartilage thickness; and higher proportional fat mass to be associated with thinner cartilage. Strongly suggesting again that it is adiposity, not bodyweight that correlated with OA progression, and even suggests that muscular tissue to be protective against joint disruption.

MRI evidence suggests decreased proteoglycan content in cartilage of obese individual, and increased cartilage deformation with acute bouts of loading (Collins, et al. 2018). Greater degrees of obesity is related to greater degrees of Hip and Knee Osteoarthritis, however, while obesity increases the rate of OA in the hip equally amongst men and women, the increased rate of knee OA is greater in women (King. et al. 2013). This suggests a probable interaction between the aforementioned disease processes and biomechanics, as women on average have a larger Q-angle than do men, although this is speculation.


It is my opinion based upon the current understanding of Osteoarthritis pathophysiology, that in many cases it may be pertinent to think of Osteoarthritis as a joint-manifestation of a systemic homeostatic imbalance. The role of systemic inflammation, obesity, and the diverse bodily effects these variables can have, independent, and in interaction with mechanical forces, shows us that a purely mechanical management strategy is likely to insufficient for many patients. In the next post in this series I will explore the ways in which mechanics, injury, and neuromuscular function can predispose, and also improve OA-related disability and pain, and how and why OA can manifest in the absence of the systemic predisposing factors.





References

Bondeson. J, Wainwright. SD, Lader. S, Amos N, Hughes. CE. (2006). The role of synovial macrophages and macrophage-produced cytokines in driving aggrecanases, matrix metalloproteinases, and their destructive and inflammatory responses in osteoarthritis. Arthritis Research and Therapy. 8(6):187


Goldring. MB, Marcu. KB. (2009). Cartilage homeostasis in health and rheumatic diseases. Arthritis Research Therapy. 11:(3):224


Dubey. NK, Ningrum. DNA, Dubey. R, Deng. YH, Wang. PD, Wang. JR, Syed-Abdul. S, Deng. WP. (2018). Correlation between Diabetes Mellitus and Knee Osteoarthritis: A Dry-To-Wet Lab Approach. International Journal of Molecular Science. 19(10):3021


Hotomisligil. GS, Shargill. NS, Spielelman. BM. (1993). Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance. Science. 259:87-91


Collins. AT, Kulvaranon. ML, Cutcliffe. HC, Uttukar. GM, Smith. WAR, Spritzer. CE, Guliak F, DeFrate. LE. (2018). Obesity alters the in vivo mechanical response and biochemical properties of cartilage as measured by MRI. Arthritis Research and Therapy. 20(1):232


Beavers. KM, Beavers. DP, Newman. JJ, Anderson. AM, Loeser. RF, Nicklas. BJ, Lyles. MF, Miller. GD, Mihalko. SL, Messier. SP. (2015). Effect of total and regional fat loss on plasma CRP and IL-6 in overweight and obese, older adults with knee osteoarthritis. Osteoarthritis and Cartilage. 23(2):249-56


Dudek, M, Gossan, N, Yang, N, Im, HJ, Ruckshanthi. JPD, Yoshitane. H, Li. X, Jin. D, Wang. P, Boudiffa. M, Bellantuono, Fukada. Y, Boot-Handford. RP, Meng, QJ. (2016). The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity. Journal of Clinical Investigation. 126(1):365-76


Mattiessen. A, Conaghan. PG. (2017). Synovitis in osteoarthritis: current understanding with therapeutic implications. Arthritis Research and Therapy. 19:18


de Vos. R, Osch. GJ, Bierma-Zeinstra. SMA, et al. (2016). Tendinopathy and osteoarthritis: a chance to kill two birds with one stone. British Journal of Sports Medicine. 50:1164-1165


Smith. MD, (2011). The normal synovium. Open Rheumatology Journal. 5:100-6


Wang. Y, Xu. J, Zhang. X, Wang. C, Huang. Y, Dai. K, Zhang. X. (2017) TNF-a induced LRG1 promotes angiogenesis and mesenchymal stem cell migration in the subchindral bone during osteoarthritis. Cell Death and Disease. 8(3):2715


Sacitharan. PK, Vincent. TL. (2016). Cellular aging mechanism in osteoarthritis. Mammalian Genome. 27:421-429


Burrage. P, Mix.KS, Brinckerhoff. CE. (2006). Matrix Metalloproteinases: Role in arthritis. Frontiers in Bioscience. 11(1):529-43.


J. Sokolove, Lepus. CM. (2013). The role of inflammation in the pathogenesis of osteoarthritis: latest findings and interpretations. Therapeutic Advances in Musculoskeletal Disease. 5(2):77-94


Robinson. HW, Lepus. CM, Wang. Q, Raghu. H, Mao. R, Lindstrom. TM, Sokolove. J. (2016). Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nature Reviews: Rheumatology. 12:580-592


Robertsson. O, Wingstrand. H, Onnerfalt. R. (1995). Intracapsular pressure and pain in coxarthrosis. Journal of Arthroplasty. 10(5):632-5


King. LK, March. L, Anandacoomarasamy. A. (2013). Obesity and Osteoarthritis. Indna Journal of Medical Research. 138(2):185-93


Coggon. D, Reading. I, Croft. P, McClaren. M, Barret. D. Cooper. C. (2001). Knee Osteoarthritis and Obesity. Journal of Obesity related Metabolic Disorders. 25:622-7


Wang. Y, Wluka. AE, English. DR. Teichtahl. AJ, Giles. GG, O’Sullivan. R. Cicuttini. FM. (2007) Body composition and knee cartilage in healthy community-based adults. Annals of Rheumatic Disease. 66(9): 1244-8


Ouchi. N, Parker. JL, Lugus. JJ, Walsh. K. (2011). Adipokinenes in inflammation and metabolic disease. Nature reviews in immunology. 11(2):85-97.


Loeser RF, Goldring SR, Scanzello CR, Goldring MB. Osteoarthritis: a disease of the joint as an organ. (2012). Arthritis Rheum. 2012; 64:1697–1707


Ishijima M, et al. Relationships between biomarkers of cartilage, bone, synovial metabolism and knee pain provide insights into the origins of pain in early knee osteoarthritis. Arthritis Res Ther. 2011; 13:R22


Pessler F, et al. The synovitis of “non-inflammatory” orthopaedic arthropathies: a quantitative histological and immunohistochemical analysis. (2008) Annals of Rheumatic Disease.


Pelletier JP, Martel-Pelletier J, Abramson SB. Osteoarthritis, an inflammatory disease: potential implication for the selection of new therapeutic targets. (2001). Arthritis & Rheumatology. 44:1237–1247

Chaganti. KR, Lane, NE. (2011). Risk factors for incident osteoarthritis of the hip and knee. Current Reviews in Musculoskeletal Medicine. 4(3):99-104


Scott. WW, Lethbridge-Cejku. M, Reichle. R, Wigley. FM, Tobin. JD, Hochberg. MC. (1993). Reliability of grading scales for individual radiographic features of osteoarthritis of the knee The Baltimore longitudinal study of aging atlas of knee osteoarthritis. Investigative Radiology. 28:497-501


Busija. L, Bridgett. L. Williams. S, Osborne. R, Buchbinder. R. (2010). Burden of musculoskeletal condition: osteoarthritis. Best Practice and Research. Clinical Rheumatology. 24:757-769