Collagen Chaos: How One Protein Explains (Almost) Everything About hEDS

Jul 11

There’s a moment many of us with hypermobile Ehlers-Danlos Syndrome (hEDS) remember vividly. It’s not the first injury, or even the first time a doctor dismissed us. It’s the moment it all starts to connect, when we learn there’s a real biological reason why our body feels like a beautiful, bizarre, frustrating mystery.

That reason?
Collagen.

Collagen is the protein holding your body together...literally. And when it’s not working the way it should, it doesn’t just cause joint issues . It affects everything in your body. Your skin and bones. Your organs and senses. Your heart rate and circulation. Your gut and bladder. Even how well your body and brain coordinate standing up and moving your limbs.

But here’s the thing: This syndrome is not some circus level flexibility and a random collection of comorbidities. It’s not imagined. It’s not even a mystery once you understand the system!

It’s biochemistry! Real, measurable, and explainable.

This post unpacks what collagen is, how it works, where it goes wrong, and how that explains the wide, weird constellation of hEDS symptoms.

🧬 What Is Collagen?

Collagen is the most abundant protein in your body, making up about 25–30% of your total protein content. It’s the main structural component of connective tissue, which acts like your body’s scaffolding, giving shape and strength to:

Joints
Tendons
Ligaments
Skin
Organs
Blood vessels
Eyes
Gums
even the basement membrane of cells! (more on that later)

Collagen is made of three protein chains that twist together into a triple helix, forming a springy, rope-like molecule. These chains can be three identical copies of the same chain (as in Type II collagen), or two of one type and one of another (as in Type I and Type V). The exact combination depends on the collagen type, but the triple-helix structure is what gives collagen its strength and stretch.

Once formed, these helices bundle into long fibers called fibrils, which provide tensile strength, (science-speak for how tissues resist being pulled or stretched without tearing).

🧪 How Is Collagen Made?

Imagine your body is trying to build a strong rope, but it can’t skip a single step, and every tool has to be just right.

Here’s how that rope (aka collagen) gets made:

Genes like COL1A1 or COL5A1 contain the instructions for different types of collagen.
These instructions are used to build early versions of the protein chains called pro-collagen.
Inside the cell, those pro-collagen chains are modified by enzymes—specialized proteins that act like molecular tools or machines, doing very specific jobs. For example:
- Hydroxylation adds chemical groups to amino acids like proline and lysine, which helps stabilize the helix.
- Glycosylation adds sugar molecules to improve solubility and structure.
- These steps require cofactors—tiny helper molecules (like vitamin C, iron, or copper) that assist enzymes in doing their jobs properly.
Three modified chains align and twist into the final triple helix.
This helix molecule is secreted (meaning the cell pushes it outside its walls), into the space around it (called the extracellular matrix).
Once outside, the collagen undergoes two key steps:
- Cleaving: Where the ends of the pro-collagen are snipped off like trimming rope ends. This step activates the molecule and allows it to assemble.
- Cross-linking: Where chemical bridges form between adjacent collagen fibrils, holding them together like rivets in a steel cable. This is what gives tissues their strength and stability.

If any step in this chain goes wrong, whether the enzymes don’t work, the cofactors are missing, or the fibrils aren’t assembled correctly, the result is weak, stretchy, or disorganized collagen.

🔬 What About the Different Types of Collagen?

There are at least 28 known types, but three are most relevant to hEDS:

Type I: Found in skin, bone, ligaments, tendons. It’s strong and tough, like rope.
Type III: Found in hollow organs and blood vessels. It’s stretchier and more delicate.
Type V: Helps regulate fibril size and structure. Think of it as the sous-chef in the collagen kitchen, making sure everything is prepped, portioned, and precisely aligned before the main fibers come together.

Problems with Type V are suspected to be a big part of hEDS, although no single gene mutation has been confirmed yet.

🧱 What’s the Basement Membrane?

The basement membrane is a thin but essential sheet of connective tissue that sits underneath the cells lining:

Skin
Blood vessels
Digestive tract
Lungs
And more

It’s made of Type IV collagen, or laminin, and other matrix proteins, and does four critical things:

Acts as biological glue to keep tissue layers connected
Functions as a filter (especially in kidneys and blood vessels)
Serves as a scaffold for growing or repairing tissue
Protects underlying structures from mechanical damage

When the basement membrane is unstable (thanks to, say, faulty collagen), it can lead to symptoms such as easy bruising, leaky blood vessels, poor wound healing and tissue fragility

📉 What Happens in hEDS?

While we don’t yet know the exact genetic cause, research suggests that hypermobile Ehlers-Danlos Syndrome (hEDS) involves subtle disruptions in how collagen is made, modified, or assembled. Some of the suspected issues include:

Defects in collagen assembly
Poor cross-linking, which weakens structural integrity
Abnormal fibril organization, leading to disorganized or fragile tissue
And potential problems with supporting matrix proteins that help collagen form correctly and stay functional

Two of those matrix proteins, tenascin-X and decorin, are currently getting a lot of attention.

Tenascin-X helps organize and stabilize collagen in the extracellular matrix (the supportive meshwork outside your cells). Without it, collagen fibers may drift apart or lose tension, contributing to overly flexible or unstable tissues.
Decorin, on the other hand, binds directly to collagen fibrils and helps regulate their spacing and alignment. You can think of it like a built-in tension cable system that keeps collagen fibers orderly and evenly distributed.

When either of these proteins is disrupted—or when collagen itself is poorly formed, the result is connective tissue that’s too stretchy, too fragile, and not nearly as resilient as it should be.

That’s why, in hEDS:

Ligaments may stretch too far and fail to stabilize joints (Side note: I spectacularly tore my ACL while riding an ATV on a volcano in Guatamala. Had I been blessed with stronger ligaments, I don't think my knee would have hyperextended enough to snap the ACL. Made it through with a great story though!)
Blood vessels might not constrict efficiently, leading to blood pooling and dizziness
Organs like the intestines can lose structural support, resulting in sluggish movement or even prolapse

It’s not something you can see on a scan, but you feel it every day. In joints that don’t quite stay where they belong. In muscles doing double duty to keep you upright. In a deep, persistent tiredness that’s hard to explain. Living with hEDS means adapting to a body that doesn’t follow the rules, but still has to function anyway.

🤕 Why Does All This Cause So Much Pain?

It’s not just the dislocations or injuries, it’s the resulting compensations!

Because your ligaments can’t stabilize your joints properly, your muscles and fascia (the web of connective tissue that wraps around and supports muscles, nerves, and organs) are constantly trying to do that job for them.

This leads to:

Muscle guarding: Muscles stay tight even when they’re not supposed to
Trigger points: Tiny knots in muscle that hurt and refer pain elsewhere
Nerve compression: Fascia or loose joints pinching nerves
Fatigue: Your nervous system is always on “high alert,” just trying to keep you upright

You’re not lazy. You’re just running a full-body stabilization effort...all the time.

🧩 How Collagen Explains the Symptom Web

Here’s how one dysfunctional protein, collagen, can ripple through nearly every system in the body. When the connective tissue framework is unstable, stretched, or poorly organized, it doesn’t just affect one part of you. It affects anything that relies on structure, support, or stability… aka, almost everything.

This table breaks down how collagen abnormalities explain the diverse, and often overwhelming range of symptoms seen in hEDS, from joint instability to cardiovascular and skin issues, and why they’re not separate problems at all, but deeply connected expressions of the same root cause.

Symptom	Tissue Affected	Collagen Type(s)	Why?
Joint hypermobility	Ligaments, tendons	I, V	Too stretchy to stabilize
Easy bruising	Blood vessels	III	Fragile walls rupture easily
POTS & dizziness	Veins, arteries	III	Can’t hold pressure → blood pools
GI issues	Gut wall, nerves, and muscles	I, III, V	Sagging structure → motility problems
Pelvic prolapse	Pelvic floor connective tissue	I, III, V	Weak hammock = falling organs
Stretchy/soft skin	Dermis	I, III, V	Fibrils disorganized
Slow healing	Basement membrane	IV	Poor anchoring + structure
Chronic pain & fatigue	Muscles, fascia, nerves	I, III, VI (likely)	Constant compensation = overuse
Dental fragility	Periodontal ligaments, enamel support	I, V	Weak root support and gingival tissue
Recurrent UTIs	Bladder walls, urethral lining	I, III	Poor structural support and impaired defense
Sound sensitivity / eardrum pain	Tympanic membrane, middle ear fascia	II, III (likely)	Overly mobile or thin tissue
Eye strain / focusing issues	Sclera, cornea, ciliary body	I, V	Lax tissue affects eye shape and pressure

🔍 Collagen Notes:

Type I is the most abundant and found in skin, tendon, vasculature, organs, and bone.
Type III is abundant in extensible connective tissues like blood vessels and hollow organs.
Type IV forms sheets, especially in the basement membrane.
Type V regulates fibril diameter, mutations here are linked to classical and hypermobile EDS.
Type VI and others (like XII) are still being studied for their role in fascial/neuromuscular connective tissue.

❤️ Final Thoughts

People with hEDS are often navigating bodies with complex blueprints and no clear manual. That doesn’t make us weak, it makes us resourceful, adaptive, and determined.

Finally understanding how your body works, on a molecular, structural, and systemic level, gives you more than just answers. It gives you the tools, the language, and the power to advocate for yourself. And more than that, it gives you the ability to share what you’ve learned, to educate the people around you, to spread awareness, and to help doctors and practitioners see what they’ve been missing.

Because this isn’t rare. It’s just rarely recognized. And we can change that.

🔗 References

Collagen Biosynthesis Overview – NCBI Bookshelf Breakdown of how collagen is made, step by step, including why vitamin C, iron, and copper are so important.
The Ehlers-Danlos syndrome: on beyond collagens (PMID: 11342567)
Deep dive into the types of collagen, how they form the triple-helix, and what roles they play in different tissues.
Structure, physiology, and biochemistry of collagens (PMID: 24443018)
Breaks down how collagen is built—from gene to triple helix—in clear steps.
Basic structure, physiology, and biochemistry of connective tissues and extracellular matrix collagens (PMID: 34807414)
Explores the different collagen types (I–VI), their three helix structure, and how they give strength to tissues.
Genetic Diagnosis of the Ehlers-Danlos Syndromes (PMID: 39629471)
Confirms that unlike other EDS types, hEDS still doesn’t have a single known gene mutation but research is ongoing.
Dysautonomia in the Ehlers-Danlos syndromes and hypermobility spectrum disorders (PMID: 34766441)
Explores the connection between hEDS and nervous system issues like POTS, dizziness, and blood pressure problems.
An overview of EDS and the link between POTS and GI symptoms (PMID: 39268060)
Details the link between hypermobile EDS and autonomic issues like POTS, dizziness, and palpitations. Also highlights how connective tissue laxity contributes to gut problems and pelvic prolapse.
Ehlers-Danlos Society: HEDGE Study Update (2024) Explains ongoing global research aimed at identifying the genetic underpinnings of hEDS. We're not there yet, but getting closer.

Jaime Prout