Below is my coverage on Tiktok on this major new discovery published just a few weeks ago. Scientists have found a potential biomarker that’s present in both Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorder. For those of you who prefer to read rather than watch, I’ve provided my script below the video.
A fascinating new study was published just a couple weeks ago, reporting on a blood-based biomarker that could potentially be used for the diagnosis of both Hypermobile Ehlers-Danlos and Hypermobility Spectrum Disorders. This may be a major leap forward in the diagnosis of these conditions, which have traditionally been diagnostically blurry and have lacked widespread genetic markers.
What’s more, the identification of this biomarker in all Hypermobile EDS and HSD samples studied strongly suggests, as many of us have been arguing for some time, that these conditions lie on a spectrum and there’s less and less justification for dividing them into two separate diagnostic categories. Hopefully, with the 2026 diagnostic updates that are scheduled, we’ll see these two entities rejoin each other, much as they used to be—as well as an expansion in diagnostic criteria that includes more of the multisystem symptoms we often experience, like dysautonomia and mast cell disorders. Hopefully, diagnosis will also become easier if a biomarker test becomes more widely available. I’m sure the scientists are already well into the patent application process, so fingers crossed they get the patent and a number of companies are interested in buying the technology!
Now, I’m not the only Tiktok creator talking about this major discovery. For instance, I recommend checking out @microcatmachine aka Allison Tennyson’s coverage on the paper itself. But I thought what I’d do here is delve a little deeper into what exactly this biomarker is and what it may mean– not only for diagnosis– but in helping us understand the common thread that may bind everyone with Hypermobile EDS and HSD together at the cellular level.
First off, you’re probably wondering what this biomarker is. The researchers found that in all 174 Hypermobile EDS and HSD participants studied, every single one of them had a fibronectin fragment that was about 52 kDa in size. (Now, “kilodaltons” just refer to the molecular weight of a molecule.) Meanwhile, this fragment wasn’t found in controls, in any of the other EDS groups studied, or in other connective tissue disorders like rheumatoid arthritis, psoriatic arthritis, or osteoarthritis.
Now, fibronectin is an important connective tissue protein that’s normally between 440 and 550 kDa in size, but it can be cleaved or snipped into smaller fragments to play a variety of different roles, such as helping with tissue remodeling after damage, promoting the formation of new blood vessels, or even serving as a signal to stimulate inflammation. There’s a wide range of sizes of fibronectin fragments, but we don’t exactly know yet what makes this 52 kDa one so special and why exactly it’s associated with Hypermobile EDS and HSD, as opposed to any other fragment sizes of fibronectin.
In an earlier study by this group of scientists, they had found that in both people with Hypermobile EDS and HSD, their fibroblasts were in what we would call a “myofibroblast-like state.” Now, fibroblasts are the cells in your body that are largely responsible for producing a lot of your connective tissue, so when it comes to EDS and HSD, these cells are important players. When damage occurs to the body, these fibroblasts spring into action, changing shape into what we call a “myofibroblast.” The “myo-“ in front of the name is a nod to “muscle.” Unlike regular fibroblasts that are in an at-rest state, these myofibroblasts have been triggered during injury and they’re able to contract, sort of like a muscle cell can, and put mechanical force on the connective tissue as it’s being rebuilt. So, think of them like a temporary microscopic Superman that holds damaged tissues together as their being repaired. And unlike the fibroblasts of other types of EDS, which don’t show this phenotype, fibroblasts in Hypermobile EDS and HSD tend to be in a myofibroblast state, suggesting there’s a very different process going on and one that’s presumably related to some kind of cellular damage.
In this earlier study, the scientists also found that when they placed these myofibroblasts from Hypermobile EDS and HSD participants into a petri dish, they were able to study the media or the solution surrounding the cells. In that media, they found all sorts of cleaved fragments of fibronectin, collagen, and tenascin. (By the way, if tenascin also sounds familiar, mutations in the tenascin-X gene are responsible for Classic-like EDS.) Anyways, these connective tissue fragments inspired the scientists to search for a blood-based biomarker that might be unique to Hypermobile EDS and HSD and that’s exactly what they’ve done.
Aside from the fact that this 52 kDa fibronectin fragment seems to be unique to Hypermobile EDS and HSD, what more can it tell us? Well, for one, we know from other studies that a similar 52 kDa-sized fragment is produced as a result of another molecule called matrix metalloproteinase-14 or MMP-14. There’s a whole bunch of MMPs and you can basically just think of them as enzymatic scissors that snip various connective tissue proteins into these smaller fragments during injury and wound repair. These MMPs are also vital for normal turnover of connective tissue proteins. We know this because animal models that are genetically engineered to lack MMP-14 have very thick, stiff, and non-elastic skin. So, these proteinases are important not only in wound healing but in normal turnover and recycling of connective tissues. Now back to the previous study, the researchers had also found, not coincidentally, a whole bunch of MMPs in the media of these Hypermobile EDS and HSD myofibroblasts.
Another interesting thing we’ve learned from other research is that MMP-14 is especially triggered when a cell is under a lot of oxidative stress. Now, what is oxidative stress? During a cell’s normal day-to-day life, it’s going to produce reactive oxygen species as a normal byproduct of cell metabolism, especially from organelles like the mitochondria, which are the powerhouses of your cells. These reactive oxygen species are molecules that contain what is basically a toxic oxygen that tends to damage many different components of the cell, like the fatty outer membrane as well as the DNA. Your cells have many ways to deal with these reactive oxygen species, some of which you get from your diet, like plant-based antioxidants. But your body also makes some antioxidants from scratch, like glutathione, which basically binds to reactive oxygen species and neutralizes them.
Now, if MMP-14 is indeed the proteinase that’s producing the 52 kDa fibronectin fragment that we’re interest in (and that’s a big “if” because of course we haven’t actually tested this in EDS, directly), it raises the question of whether fibroblasts in Hypermobile EDS and HSD are under a lot of oxidative stress. There are many different metabolic issues that could promote excessive oxidative stress, like impairments to the mitochondria or problems with another organelle called the lysosome, which is basically part of your cellular trash and recycling. That means there could be a wide variety of different genotypes that then could be responsible because a lot of people are carriers for these kinds of metabolic diseases. This in turn could help explain why there are soooo many more people with Hypermobile EDS and HSD compared to the other types of EDS.
Okay, so, this last part is speculative. But to me, at least, it suggests that Hypermobile EDS and HSD are probably degenerative diseases. Fibrodegenerative diseases to be exact. Think of it sort of like Alzheimer’s but in your connective tissue. And, actually, some of our work on fragile X premutation suggests exactly this. We’ve identified a subset of women with the premutation who have either Hypermobile EDS or HSD phenotypes. Interestingly, we already know that the premutation is partly a degenerative disorder, thanks to toxic build-up of RNA and proteins that end up really stressing the cells out. So, it’ll be interesting to see how this area of research blossoms in coming years. I’m really looking forward to it.
Anyways, those are my thoughts on the subject for now. I do really think that a substantial subset, if not all, people with Hypermobile EDS and HSD have a fibrodegenerative disease—aka a degenerative disease of the fibroblasts. But only time and more research will tell if that’s actually the case. So, we’ll see!
Thanks again for following me down this winding science rabbit role. And until next time… ciao!