Tendinitis Genes

Do you have problems with your tennis elbow, rotator cuff, knees, or Achilles tendon? If so, you’ve probably followed the usual advice of rest, ice, and keeping it immobile. Then you wait and hope that it heals. One of the reasons there are very few, if any, effective treatments for tendinopathy is a lack of knowledge regarding its pathogenesis. In other words, we didn’t know much about how tendinopathy works until recently.

This article digs into the mechanisms that cause tendonitis, explains what is going on in the tendon, and then shows you how your genes influence the risk of having tendon problems. I’ll conclude with genetic-specific possible solutions.

What is tendinitis and why does it happen?

Tendons are the rope-like connective tissue that connects a muscle to a bone. They are the connection that moves the joint, transmitting forces from the muscle to the bone.

Tendon injuries are common and can include:

  • tendinitis (or tendinopathy) is an inflamed tendon
  • torn tendons

Tendinitis can occur in almost any tendon in the body, and many different terms refer to these issues. Examples include:

  • tennis elbow or golfer’s elbow
  • plantar fasciitis (bottom of the foot)
  • Achilles tendonitis (ankle)
  • trigger finger (tendonitis in the index finger)
  • rotator cuff injury (shoulder)
  • patellar (knee) tendonitis

There seems to be a lack of good treatment options for such common injuries. The Cleveland Clinic recommends: rest, icing, taking NSAIDs, and seeing your doctor if it still hurts in three weeks.[ref]

It is 2022! Why don’t we have better options for treatment?

A research study on tendon injuries explains:[ref]

“One of the reasons there are very few, if any, effective treatments for tendinopathy is lack of knowledge regarding its pathogenesis.”

So let’s dig into the ‘pathogenesis’, or the underlying changes in tendon injuries, and see what is causing the problems.

Changes seen in tendinitis:

When looking at a normal tendon, it is white and has a firm elastic texture. Tendons are made up of parallel and organized collagen bundles.

In tendonitis, though, the tendon is gray or brown and is thin and fragile. The collagen bundles that make up the tendon are disorganized, meaning that under a microscope, they show up as varying in diameter and not oriented in the same direction. Healthy tendons don’t have a lot of blood flow, but in tendonitis, the tendon has ingrowths of small blood vessels and small nerves.[ref]

Here’s an image showing how the collagen fibers should be organized in a tendon:

CC Image https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865563/

 

Let’s take a closer look at the components of healthy tendons:

Extracellular matrix, collagen, and tendon structure:

The extracellular matrix (ECM) surrounds and supports cells in your body. The ECM consists of:

  • structural proteins (collagen, elastin)
  • specialized proteins (fibrillin, fibronectin)
  • proteoglycans

The ECM is vital in the composition of the tendon, giving the structure around the tendon cells. Tendon cells are a specialized type of fibroblast, which are cells that produce the extracellular matrix.

Collagen in the extracellular matrix is what makes up most of the tendon. There are a bunch of types of collagen, but the primary ones in tendons are type I, type III, and type IV. In addition to collagen, the ECM in tendons also contains a little cartilage, elastin, and proteoglycans.

Proteoglycans are proteins bound to strings of carbohydrate molecules. In the ECM, proteoglycans help increase the tendon’s water content, which helps to resist compression.[ref] In my mind, proteoglycans are like jello, keeping the tendon spongy yet firm.

The type of polysaccharide (carbohydrate) attached to proteoglycans is glycosaminoglycans. It may sound familiar to anyone looking at glucosamine supplements marketed for joint health.

Remodeling of tendons: dynamic and continuing.

The extracellular matrix in tendons isn’t a static, fixed thing. A tendon is thought to be rope-like, but there is constant turnover and remodeling. Parts of the ECM are degraded and recycled, while at the same time, new ECM is synthesized.[ref]

Matrix metalloproteinases (MMP) are enzymes that completely degrade connective tissue and modify the extracellular matrix. Just as there are several types of collagen, several different MMP enzymes also break down collagen.

ADAMs (a disintegrin and metalloproteinase) are enzymes that can break down the non-collagen parts of tendons and signal for the assembly of collagen fibrils.

What happens when a tendon is injured?

Tendon repair occurs in stages, beginning with an inflammatory stage that lasts for a few days. The repair process then takes weeks to months to complete.

Growth factors are signaling molecules that are released in the area of an injury. IGF1 (insulin growth factor 1) and TGFβ (transforming growth factor beta) are activated almost immediately in an injury. They remain active throughout most phases of tendon healing.

Researchers think that IGF1 is signaling to stimulate new fibroblasts to the injury site and promote the production of the extracellular matrix during remodeling. PDGF (platelet-derived growth factor) is involved in the initial stages of the injury, and it initiates more collagen production as well as increases IGF1.

After the initial injury phase, VEGF (vascular endothelial growth factor) increases and helps to form new, small blood vessels that bring nutrients to the injured tendon.[ref]. Combinations of genetic variants in the genes that encode VEGF are linked to a greater risk of tendinopathy.[ref]

Repetitive use and cell death:

Tendon ruptures, such as tearing an Achilles tendon, rarely happen as an acute injury (even though it seems to happen that way). Instead, tendons that tear usually show prior remodeling, microtraumas, and disordered collagen.[ref] The tendons have had strain and stress with inflammation and remodeling before the tear occurs.

Apoptosis is the process of cell death that goes on regularly in the body as old cells need to be replaced by new cells. Research shows that repetitive strain causes increased apoptosis (cell death) of the fibroblasts responsible for creating the ECM.[ref] While apoptosis is a normal part of the cell lifecycle, excess apoptosis can be a problem.

Chronic inflammation in tendinitis:

Doctors used to think that inflammation wasn’t a part of the degeneration in tendinitis, but research over the last decade or so shows that this is simply not true. Instead, an overwhelming amount of recent research shows that inflammation is an integral part of the problem in tendinopathies.[ref]

  • Animal studies show that injecting inflammatory cytokines into a tendon can cause reduced tensile strength and increased tears over the course of several months.[ref]
  • Biopsies of Achilles tendons show that people with Achilles problems have chronic, non-resolving inflammation. The injured/torn Achilles showed higher levels of IL-8, NF-κB, interferon, and PTGS2. Researchers theorize that the key to preventing further Achilles injuries is ensuring inflammation resolution.[ref]. (More on this in the lifehacks section — as well as this article on the resolution of inflammation as an active process.)

Inflammatory cytokines are an essential part of the initial response to injury. But researchers are finding that overall chronic inflammation, such as due to lifestyle factors, impairs the healing of tendons after the initial response (first couple of days).[ref] In fact, tendon problems are more common in people with chronic inflammatory conditions, such as obesity or smoking.[ref][ref]

IL-1B, an inflammatory cytokine, and MMP-1, the matrix metalloproteinase that breaks down collagen, can both be produced by tenocytes, the tendon cells that create the extracellular matrix. This production initiates two different pathways:

  • The increase in IL-1B causes a cascade of inflammatory events, such as activating NF-κB.
  • Elevated MMP-1 breaks down collagen in the tendon faster than it is being produced.[ref]

As I mentioned above, matrix metalloproteinases (MMPs) are enzymes that can break down collagen. MMP-1, MMP-8, and MMP-13 can degrade type I and type III collagen. Genetic variants that increase MMP-1, -8, and -13 are linked to an increased risk of tendon problems.

Inflammation in the tendon due to repetitive strain increases PGE2 (prostaglandin E2). It causes a ‘double whammy’: Prostaglandin E2 increases MMP-1 (increasing collagen breakdown) and inhibits collagen synthesis.[ref]

Additionally, research shows that in torn or damaged tendons, there is an increase in inflammatory cell types such as macrophages, mast cells, T-lymphocytes, and natural killer cells.[ref]

Recently published research points to a protein called CTRP3 as potentially important in tendinopathies. Researchers are still determining all that CTRP3 (C1q/tumor necrosis factor (TNF)–related protein-3) does, but currently, the understanding is that it is the regulation of inflammation and cell growth, including in tendons. The new research found that CTRP3 is markedly upregulated in tendinopathies, pointing again toward the importance of inflammation in tendon problems.[ref]

Taken together, recent research suggests that chronically elevated inflammation plays a significant role in the pathogenesis of tendon problems.

The continuation of elevated inflammatory cytokines — coinciding with the lack of resolution of inflammation — leads to remodeling, breakdown, and eventually disorganized collagen fibers in the tendons.


Genetic variants related to tendon problems:

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Genetics plays a role in both the tendon’s formation and the propensity for chronic inflammation. Genetic variants can also increase (or decrease) the MMP enzymes that break down collagen.

GDF5 Gene: This gene encodes a growth factor involved in bone and cartilage formation. Variants in GDF5 are associated with an increased risk of Achilles tendon tears.

Check your genetic data for rs143383 (i6011281) (23andMe v4, AncestryDNA)

  • A/A: higher risk of Achilles tendon (common genotype)[ref]
  • A/G: less of a risk of Achilles tendon problems
  • G/G: half the risk of Achilles tendon problems

Members: Your genotype for rs143383 is .

COL1A2 gene: encodes part of the type 1 collagen protein

Check your genetic data for rs1800012 (23andMe v4, v5):

  • C/C: typical
  • A/C: typical risk for Achilles tendon tear
  • A/A: significantly reduced risk of Achilles tendon tear[ref]

Members: Your genotype for rs1800012 is .

COL5A1 gene: encodes a collagen formation protein involved in tendon formation. Rare mutations in this gene are linked to Ehler’s Danlos Syndromes. (Check your genes in the EDS article)

Check your genetic data for rs12722 BstUI (23andMe v4, v5):

  • C/C: half the risk of Achilles tendinopathy (higher levels of COL5A1)[ref][ref]
  • C/T: higher risk of Achilles tendinopathy (lower levels of COL5A1); increased risk of tennis elbow
  • T/T:​ higher risk of Achilles tendinopathy (lower levels of COL5A1)[ref]; increased risk of tennis elbow[ref]

Members: Your genotype for rs12722 is .

MIR608 gene: microRNA 608 interacts with COL5A1 in collagen formation

Check your genetic data for rs4919510 (AncestryDNA):

  • C/C: typical
  • C/G: associated with chronic Achilles tendinopathy
  • G/G: associated with chronic Achilles tendinopathy[ref]

Members: Your genotype for rs4919510 is .

Inflammation-related genetic variants linked to tendinopathy:

BMP4 gene: encodes bone morphogenetic protein 4, a growth factor in the TGF-beta family that plays a role in neurogenesis, vascular development, and bone development.

Check your genetic data for rs2761884 (23andMe v4, v5)

  • G/G: typical
  • G/T: increased risk of tendinopathies
  • T/T: 2-fold increased risk of tendinopathies[ref]

Members: Your genotype for rs2761884 is .

FCRL3 gene: encodes an Fc receptor protein that plays a regulatory role in the immune system. Variants in this gene are linked to rheumatoid arthritis and other autoimmune diseases.

Check your genetic data for rs7528684 (23andMe v4, v5; AncestryDNA):

  • A/A: typical
  • A/G: increased risk of tendinopathies
  • G/G: increased risk of tendinopathies[ref]

Members: Your genotype for rs7528684 is .

TNF gene: encodes the inflammatory cytokine TNF-alpha

Check your genetic data for rs1800629 -308A/G (23andMe v4, v5; AncestryDNA):

  • A/A: Higher TNF-alpha levels; increased risk of Achilles tendon problems and knee tendon problems[ref]
  • A/G: somewhat higher TNF-alpha levels; increased risk of Achilles tendon problems and knee tendon problems
  • G/G: typical, better response to high protein/low carb diet

Members: Your genotype for rs1800629 is .

Matrix metalloproteinase gene variants linked to increased risk of tendinopathy:

MMP13 gene:

Check your genetic data for rs2252070 (23andMe v4; AncestryDNA):

  • T/T: common genotype; increased risk of posterior tibial tendon problems (flat foot)[ref]
  • C/T: increased risk of posterior tibial tendon problems (flat foot)
  • C/C: decreased risk of posterior tibial tendon problems (flat foot)

Members: Your genotype for rs2252070 is .

MMP1 gene: matrix metalloproteinase-1 is involved in remodeling collagen type I, III, and V.

Check your genetic data for rs1144393 (23andMe v4; AncestryDNA):

  • C/C: increased risk of posterior tibial tendon problems[ref]
  • C/T: increased risk of posterior tibial tendon problems
  • T/T: decreased risk of posterior tibial tendon problems

Members: Your genotype for rs1144393 is .

MMP3 gene: matrix metalloproteinase-3 is involved in the remodeling of collagen.

Check your genetic data for rs650108 (AncestryDNA)

  • G/G: increased risk of tendinopathies (high-level athletes)[ref]
  • A/G: typical risk
  • A/A: typical risk

Members: Your genotype for rs650108 is .

Check your genetic data for rs679620 (23andMe v4, v5; AncestryDNA):

  • T/T: increased risk of tendinopathies (high-level athletes)[ref]
  • C/T: typical risk
  • C/C: typical risk

Members: Your genotype for rs679620 is .

 


Lifehacks:

Research on tendinopathy is extensive and ongoing. Below are just a few of the recent studies on ways to treat or prevent tendon issues.

Drugs that increase tendinopathy:

Medications can interact with the matrix metalloproteinase enzymes and increase collagen turnover in the tendon.

  • Statins are known to increase the risk of tendon problems. One study found a 50% increase in relative risk of trigger finger and a ~40% increased risk of shoulder tendinopathy with statin use. Experiments showed an increased release of MMP-1 and MMP-13 with simvastatin, which weakened and disrupted the tendon matrix.[ref]
  • Fluoroquinolone antibiotics also are linked to an increased risk of tendinopathy, with Achillies tendon ruptures being the most common problem. The onset of tendon problems can happen weeks to months after taking fluoroquinolones.[ref]

MMP inhibitors:

Just as some drugs can increase MMPs, other drugs may benefit by inhibiting the breakdown of collagen in tendons. (Natural MMP inhibitors are listed below in the supplements section).

  • Doxycycline: The commonly used antibiotic, doxycycline, inhibits the matrix metalloproteinase. Animal studies show that doxycycline may help repair Achilles tendon injuries and improve collagen filament integrity.[ref]

Platelet-rich plasma injections:

A common treatment for tendon issues is injections of platelet-rich plasma. But does it work? A meta-analysis of 29 studies found that platelet-rich plasma injections were likely better than doing nothing (wait-and-see method).[ref]

Polyphenol-rich Diet:

A flavonoid-rich diet may help to reduce overall inflammation. Fresh fruits and vegetables, such as blueberries, red peppers, parsley, and citrus fruits, are suggested as good sources of flavonoids that may help with tendinitis.[ref]

Natural supplements for tendinitis:

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Related Articles and Genes:

TNF-alpha: Inflammation and Your Genes
Do you feel like you are constantly dealing with inflammation? Joint pain, food sensitivity, etc.? Perhaps you are genetically geared towards a higher inflammatory response. Tumor necrosis factor (TNF) is an inflammatory cytokine that acts as a signaling molecule in our immune system.

NLRP3 Inflammasome, Genetics, and Chronic Inflammation
What makes people more susceptible to chronic inflammatory diseases? The root of the over-activation of inflammation for some people could be the NLRP3 inflammasome.

C-Reactive Protein Gene: Marker of Inflammation
Chronic inflammation is the driver of many common diseases such as heart attacks, diabetes, obesity, and autoimmune diseases. C-Reactive Protein is a marker of inflammation. Genetic variants can increase or decrease CRP levels.

Will statins give you muscle pain? What your genes can tell you
Statins are one of the most prescribed medications in the world. One side effect of statins is myopathy, or muscle pain and weakness. Your genetic variants are significant in whether you are likely to have side effects from statins.

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About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.