Taming the Zebra – Excerpt 2

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Excerpt from: Taming the Zebra – It’s Much More than Hypermobility: The Definitive Physical Therapy Guide to Managing HSD/EDS, Volume 1 Systemic Issues and General Approach 

(Due out Winter of 2023)

Fibroblasts and the ECM (Extracellular Matrix)

Those patients with a structurally-compromised ECM – whether from collagen or proteoglycan
abnormalities – often demonstrate the impaired connective tissue function that we see in
connective tissue disorders (Hypermobility Spectrum Disorder, EDS, Marfan’s Syndrome, etc).
Recent research has proposed that different types of EDS can be attributed to different disorders in the ECM. This research has further identified a common cause of fibroblast dysfunction amongst all subtypes of HSD/EDS. Fibroblasts synthesize collagen, create the architecture of the ECM, and play a role in regulating inflammation. So, if fibroblasts do not work properly, neither will the ECM or any system that depends on the ECM.

For example, Malek and Koster (2021) proposes three factors contributing to the connective
tissue dysfunction: receptor interaction, integrin switch abnormalities, and fibroblast dysfunction.

The first issue is a failed interaction between collagen and its receptor, which seems to be
dictated by what type of subgroup of EDS the patient may have. For example, classical EDS is
associated with dysfunction in the type V and I collagen components of the ECM.

The second factor, the integrin switch, is common in other HSD/EDS subtypes. Here, when a
system recognizes the dysfunctional collagen-ECM adhesion, in response, fibroblasts may
compensate by encouraging the cell to adhere to different structures, like fibronectin rather than collagen, as it goes into “survival mode”. This will, unfortunately, feed into the dysfunctional fibroblastic activity.

The third factor concerns dysfunction found within the fibroblast itself. Not only is there an issue
with the fibroblast itself due to the genetic variation suspected, but HSD/hEDS is proposed to
additionally have issues with cell adhesion in the ECM due to the dysfunctional fibroblasts.
Impaired cell-ECM adhesion further impedes the fibroblasts from being able to regulate
homeostasis within their environment (the ECM and connective tissue).

A newer body of research offers that the pathomechanism of the HSD/EDS spectrum as
a whole may be linked to three stages of dysfunction. First, the specific type of EDS or
HSD will dictate the cause of failure between collagen and its receptor. Second, the main
types of HSD/EDS show a response of the integrin switch that recognizes the faulty
collagen-ECM connection and goes into survival mode, binding other ECM ligands
rather than collagen in an attempt to maintain homeostasis and prevent cell death. The
last stage is dysfunction within the fibroblast itself in hEDS, causing abnormal
connective tissue make-up.

Mechano-Sensitivity and Load Tolerance

There are downstream effects on the ECM structure and function due to altered signals when
cells cannot adhere in the usual way or when the structure of collagen is altered. One
downstream issue is increased “mechano-sensitivity”, which is a response to a mechanical
stimulation on the structure.

The ECM in those with EDS has been found to tolerate much lower loads before cells separate
compared to normal ECM. In normal conditions, the ECM responds to loads by becoming
stronger. More research is needed on how the ECM responds to loads in patients with EDS.
Strengthening studies on patients with HSD/EDS report improved strength, pain, proprioception, perceived function of daily living, and stiffness of joints and tendons, indicating that those with HSD/EDS can benefit from strengthening exercises (see Chapter 19). There is a relatively high dropout rate in the studies and we cannot rule out discomfort with the prescribed exercise program as one of the challenges. It is possible that new parameters for strength exercise progression will need to be created that are specific to HSD/EDS, recognizing the difference in ECM response to load. At this point, anecdotal evidence suggests starting with lighter loads/weights and progressing more slowly than standards set out by the American Academy of Sports Medicine with a lower maximum load at the end of the progression to prevent iatrogenic injuries. This may show a more positive response to a strengthening program as there is less load imposed on the ECM with a slower acclimation period, allowing the compromised ECM to adapt more efficiently.