Osteoarthritis—Knowing the Basics

An estimated 10 to 15% of all adults aged over 60 have some degree of osteoarthritis (OA), with prevalence higher among women than men. According to the United Nations, by 2050, people aged over 60 will account for more than 20% of the world’s population.

Figure 1.  Synovial fluid (By Madhero88)

Osteoarthritis (OA)

Osteoarthritis (OA) is a degenerative disease of the articular joints with progressive nature involving the synovium, articular cartilage, and subchondral bone(see Figure 1).  It is characterized by the breakdown of cartilage, joint lining, ligaments, and underlying bone. It typically involves an entire joint, with the most commonly affected joints being the hips, knees, hands, and spine. 

Common manifestations of OA are stiffness and pain. There are a variety of risk factors for OA, including:^[3] 

• High-impact sports
• Obesity
• The risk of suffering osteoarthritis can be decreased with weight loss. 
• This reduction of risk is related in part with the decrease of the load on the joint, but also in the decrease of fatty mass, the central adipose tissue and the low-level inflammation associated with obesity and systemic factors.
• Bone deformities

The prevalence of OA increases with obesity and age.^[4,5]  Knee OA is the most leading cause of disability and pain in the adult and old age population.

Figure 2.  Bone Grown (cancellous bone vs cortical bone)

Research Highlights

• Levels of several inflammatory mediators, such as IL-6 and CCL2 (belongs to the CC chemokine family), were higher in OA sera compared to healthy sera^[16]
• Which suggest the inflammatory nature of OA
• CCL2 recruits monocytes, memory T cells, and dendritic cells to the sites of inflammation produced by either tissue injury or infection.
• CCL2 is implicated in pathogeneses of several diseases characterized by monocytic infiltrates, such as psoriasis, rheumatoid arthritis and atherosclerosis.
• Read here for a summary of dietary interventions that may be of benefit in OA
• Obesity leads to low-grade systemic inflammation and weight reduction can reduce adipose tissue and restore normal secretion patterns.^[13]
• Leptin is associated with inflammation and cartilage degradation and may be involved in OA pathophysiology at a local and systemic level.^[14-15]
• Leptin can affect bone metabolism via direct signaling from the brain. 
• Leptin decreases cancellous bone, but increases cortical bone (see Figure 2). This "cortical-cancellous dichotomy" may represent a mechanism for enlarging bone size, and thus bone resistance, to cope with increased body weight.
• In a cell study with human chondrocytes (cells that make up cartilage), the anti-inflammatory action of IL-10 protects against damage from tumor necrosis factor-alpha (TNF-α), a pro-inflammatory mediator elevated in OA.^[1] 
• In another study, it shows that bioavailable turmeric extract is as effective as paracetamol in reducing pain and other symptoms of knee OA and found to be safe and more effective in reducing CRP and TNF-α.^[3]

TNF Promotes Inflammatory Response

Tumor Necrosis Factor (TNF) promotes the inflammatory response, which, in turn, causes many of the clinical problems associated with autoimmune disorders such as

• Rheumatoid arthritis
• Ankylosing spondylitis
• Inflammatory bowel disease
• Psoriasis
• Hidradenitis suppurativa
• Refractory asthma. 

These disorders are sometimes treated by using a TNF inhibitor. On the other hand some patients treated with TNF inhibitors develop an aggravation of their disease or new onset of autoimmunity.  In one study, it provides some evidence that acute exercise may inhibit TNF production.^[6]

TNF seems to have an immunosuppressive facet as well. One explanation for a possible mechanism is this observation that TNF has a positive effect on regulatory T cells (Tregs), due to its binding to the tumor necrosis factor receptor 2 (TNFR2).^[7]

TNF-α and IL-6 concentrations are elevated in obesity.^[8-10]  Monoclonal antibody against TNF-α is associated with increases rather than decreases in obesity, indicating that inflammation is the result, rather than the cause, of obesity.^[10]

Figure 3.  Schematic diagram of the proposed mode of action for type II collagen (UC-II) 

UC-II®

UC-II® contains active epitopes that are able to interact with Peyer’s patches and induce oral tolerance.  A possible mechanism of action for UC-II activity is briefly summarized below (see Figure 3):

1. Transforms naïve T-cells into Treg 
• When consumed, UC-II® is believed to be taken up by the Peyer’s patches, where it activates immune cells. It transforms naive T-cells into T regulatory (Treg) cells that specifically target type II collagen. 
2. Treg cells then migrate through the circulation
3. Encounters type II collagen in joint cartilage
• When they recognize type II collagen in joint cartilage, Treg cells secrete anti-inflammatory mediators (cytokines), including TGF-β, IL-4 and IL-10. 
• Note that the effect of TGF-β has been shown to be highly context-dependent.^[11]
• This action helps reduce joint inflammation and promotes cartilage repair. 

This process initiates anti-inflammatory and cartilage protective pathways that prevent the immune system from injuring its joint cartilage while promoting cartilage repair and regeneration. 

Summary of cytokines and their functions

Cytokine	Family	Main sources	Function
IL-1β	IL-1	Macrophages, monocytes	Pro-inflammation, proliferation, apoptosis, differentiation
IL-4	IL-4	Th-cells	Anti-inflammation, T-cell and B-cell proliferation, B-cell differentiation
IL-6	IL-6	Macrophages, T-cells, adipocyte	Pro-inflammation, differentiation, cytokine production
IL-8	CXC	Macrophages, epithelial cells, endothelial cells	Pro-inflammation, chemotaxis, angiogenesis
IL-10	IL-10	Monocytes, T-cells, B-cells	Anti-inflammation, inhibition of the pro-inflammatory cytokines
IL-12	IL-12	Dendritic cells, macrophages, neutrophils	Pro-inflammation, cell differentiation, activates NK cell
IL-11	IL-6	Fibroblasts, neurons, epithelial cells	Anti-inflammation, differentiation, induces acute phase protein
TNF-α	TNF	Macrophages, NK cells, CD4+lymphocytes, adipocyte	Pro-inflammation, cytokine production, cell proliferation, apoptosis, anti-infection
IFN-γ	INF	T-cells, NK cells, NKT cells	Pro-inflammation, innate, adaptive immunity anti-viral
GM-CSF	IL-4	T-cells, macrophages, fibroblasts	Pro-inflammation, macrophage activation, increase neutrophil and monocyte function
TGF-β	TGF	Macrophages, T cells	Anti-inflammation, inhibition of pro-inflammatory cytokine production

References

1. Müller R.D., John T., Kohl B., Oberholzer A., Gust T., Hostmann A., Hellmuth M., Laface D., Hutchins B., Laube G., et al. IL-10 overexpression differentially affects cartilage matrix gene expression in response to TNF-alpha in human articular chondrocytes in vitro. Cytokine. 2008;44:377–385.
2. Transmission, pathogenesis, replication of SARS-CoV-2 (COVID-19)
3. Bioavailable turmeric extract for knee osteoarthritis: a randomized, non-inferiority trial versus paracetamol
4. Altman R, Asch E, Bloch G, et al. Development of criteria for the classification and reporting of osteoarthritis: classification of osteoarthritis of the knee. Arthritis Rheum. 1986;29:1039–49.
5. Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res. 2012;64:465–74.
   
6. Pedersen BK (December 2009). "The diseasome of physical inactivity – and the role of myokines in muscle–fat cross talk". J Physiol. 587 (23): 5559–5568.
7. Salomon BL, Leclerc M, Tosello J, Ronin E, Piaggio E, Cohen JL (2018). "Tumor Necrosis Factor α and Regulatory T Cells in Oncoimmunology". Front. Immunol. 9: 444.
8. Coppack SW (August 2001). "Pro-inflammatory cytokines and adipose tissue". The Proceedings of the Nutrition Society. 60 (3): 349–56.
9. Kern L, Mittenbühler MJ, Vesting AJ, Wunderlich FT (2018). "Obesity-Induced TNFα and IL-6 Signaling: The Missing Link between Obesity and Inflammation-Driven Liver and Colorectal Cancers". cancers. 11(1): 24.
10. Virdis A, Colucci R, Bernardini N, Masi S (2019). "Microvascular Endothelial Dysfunction in Human Obesity: Role of TNF-α". The Journal of Clinical Endocrinology and Metabolism. 104 (2): 341–348.
11. Wahl SM (February 2007). "Transforming growth factor-beta: innately bipolar". Current Opinion in Immunology. 19 (1): 55–62.
12. What is the evidence for a role for diet and nutrition in osteoarthritis
13. Hauner H. Secretory factors from human adipose tissue and their functional role. Proc Nutr Soc. 2005 May; 64(2):163-9.
14. Leptin produced by joint white adipose tissue induces cartilage degradation via upregulation and activation of matrix metalloproteinases.
15. Leptin in osteoarthritis: Focus on articular cartilage and chondrocytes.
16. Sohn DH, Sokolove J, Sharpe O, Erhart JC, Chandra PE, Lahey LJ, Lindstrom TM, Hwang I, Boyer KA, Andriacchi TP, et al. Plasma proteins present in osteoarthritic synovial fluid can stimulate cytokine production via Toll-like receptor 4. Arthritis Res Ther. 2012;14:R7.
17. Slide show: Hand exercises for people with arthritis (Mayo Clinic)
18. Sulforaphane represses matrix-degrading proteases and protects cartilage from destruction in vitro and in vivo
• Sulforaphane can be found in cruciferous vegetables like broccoli, kale, cabbage, and watercress.