Connective Tissue Disorders/Ehler Danlos, the ECM and Chronic Issues - MCAS, CIRS, POTS, CFS, IBS, Dystonias, Pain, Proprioceptive Disorders, ETC.!

[worldbridger]

Wrote an intro on this subject here:

Ehlers-Danlos Syndrome Shines Light on Our Most Sensory Organ

Connective Tissue Disorders Also Key to Understanding 'Miracle Cures'

healthmatrixnet.substack.com

https://twitter.com/x/status/1964432332351578315

Alternative practitioners, who have mastered non-mainstream treatments to deal with problems at the level of the connective tissue and its relation to the autonomic nervous system, witness miracle cures every day.

They have learned to expect "action at a distance" and have understood why throughout the decades.

I once believed that the autonomic nervous system was the most unrecognized system in Western medicine, but now I think connective tissue (or fascia) takes that position.

Fascia houses 25% more nerve endings than skin, and 1,000% more than the collective innervation of muscle, so fascia could very well be considered our richest sensory organ.

Just as cell membranes (cell "mem-brain") are known to be of critical importance for the cell itself to the point that some consider it the cell's real brain, fascia/connective tissues have "mem-brain" like properties for everything that they connect with and encapsulate.

Understanding Ehler Danlos Syndrome is a lesson in understanding connective tissue.

Learning about miracle cures developed 100 years ago by physiologists can teach us a lot about the connective tissue and the autonomic nervous system. For more information, see: Ehlers-Danlos Syndrome Shines Light on Our Most Sensory Organ

Does Marcaine works too, or does it have to be Procaine?

 

[Gaby]

What seems to help me to keep in check some of these symptoms is watching my diet, exercising almost daily (very important) also, taking B complex, B1, Omega 3 and Mind+ helps a lot.

It seems to me that you have conjunctive tissue disorders that stemmed from after the COVID-19 era. Long COVID really brought some of the experience that EDS or fibromyalgia patients have to a large segment of the population. I was puzzled to see that people were puzzled that they had fatigue after a viral infection. I sometimes joked with some of my patients, "welcome to my world and how I felt for my entire life".

EDS have very specific clinical signs that can be identified upon physical examination, including hypermobile joints and atrophic scars, piezogenic papules on the feet, etc. EDS is really something you're born with, and there are already signs and symptoms throughout childhood.

Does Marcaine works too, or does it have to be Procaine?

For neural therapy, only procaine and lidocaine will do. It has to do with their chemical properties, half life, their structural signature, etc.

Procaine is way preferable than lidocaine.

 

[worldbridger]

It seems to me that you have conjunctive tissue disorders that stemmed from after the COVID-19 era. Long COVID really brought some of the experience that EDS or fibromyalgia patients have to a large segment of the population. I was puzzled to see that people were puzzled that they had fatigue after a viral infection. I sometimes joked with some of my patients, "welcome to my world and how I felt for my entire life".

EDS have very specific clinical signs that can be identified upon physical examination, including hypermobile joints and atrophic scars, piezogenic papules on the feet, etc. EDS is really something you're born with, and there are already signs and symptoms throughout childhood.


For neural therapy, only procaine and lidocaine will do. It has to do with their chemical properties, half life, their structural signature, etc.

Procaine is way preferable than lidocaine.

I tried this 8 years ago, only doctor in Sweden that does this, but he only uses Marcaine, maybe the reason it didn't work. Procaine is not available or not registered in Sweden anymore.

 

[Gaby]

I synthesized the subject of Mast Cell Activation Syndrome here:

What's wrong with my immune system? When connective tissue inflammation 'explains the unexplainable'

Mast cell activation syndrome (MCAS) - An inflammatory condition and immunological disease characterized by mast cell dysregulation in connective tissue

healthmatrixnet.substack.com

 

[Cordillera]

I synthesized the subject of Mast Cell Activation Syndrome here:

What's wrong with my immune system? When connective tissue inflammation 'explains the unexplainable'

Mast cell activation syndrome (MCAS) - An inflammatory condition and immunological disease characterized by mast cell dysregulation in connective tissue

healthmatrixnet.substack.com

View attachment 112544

This is the most revealing article I've read about my symptoms since discovering I have dysautonomia with hyperflexibility.

I've already shared it with family and friends.

Thanks, Gaby

 

[Gaby]

Some people in this forum have benefited from low dose doxy. I have benefited enormously from the standard dose of 200 mg per day. I decided to take it around 10 years ago, motivated by research and also when a correspondent and one of the leading researchers of the "The Gulf War Syndrome" suggested that I take it to see if my symptoms improve.

Back then, I suspected that my problems were compounded by the vaccines I took as a requirement for University (medical school). By the time I was finished, I saw benefits in concentration, pain, energy levels, sleep, etc. Now I know that my extracellular matrix is particularly dysfunctional.

Here's more evidence that it prevents collagen degradation, particularly in those with a dysfunctional extracellular matrix:

https://www.mdpi.com/2073-4409/10/11/3236

Hypermobile Ehlers-Danlos syndrome (hEDS) is the most frequent type of EDS and is characterized by generalized joint hypermobility and musculoskeletal manifestations which are associated with chronic pain, and mild skin involvement along with the presence of more than a few comorbid conditions. Despite numerous research efforts, no causative gene(s) or validated biomarkers have been identified and insights into the disease-causing mechanisms remain scarce. Variability in the spectrum and severity of symptoms and progression of hEDS patients’ phenotype likely depend on a combination of age, gender, lifestyle, and the probable multitude of genes involved in hEDS. However, considering the clinical overlap with other EDS forms, which lead to abnormalities in extracellular matrix (ECM), it is plausible that the mechanisms underlying hEDS pathogenesis also affect the ECM to a certain extent. Herein, we performed a series of in vitro studies on the secretome of hEDS dermal fibroblasts that revealed a matrix metalloproteinases (MMPs) dysfunction as one of the major disease drivers by causing a detrimental feedback loop of excessive ECM degradation coupled with myofibroblast differentiation. We demonstrated that doxycycline-mediated inhibition of MMPs rescues in hEDS cells a control-like ECM organization and induces a partial reversal of their myofibroblast-like features, thus offering encouraging clues for translational studies confirming MMPs as a potential therapeutic target in hEDS with the expectation to improve patients’ quality of life and alleviate their disabilities.

As a further proof of the valuable effect of doxy restoring the ECM organization and reverting the hEDS myofibroblast-like phenotype, we repeated the treatment of control fibroblasts with hEDS and control CM under the same time reference points reported in Figure 1A but supplementing the CM with 50 µM of doxy. As shown in Figure 4, in the presence of doxy, the hEDS-CM was not able to exert its degradative and differentiation activity, since control fibroblasts maintained a proper ECM organization and did not acquire the typical cellular features of patients’ cells.

The ECM regulates tissue architecture and homeostasis as it provides chemical and mechanical signals to cells modulating their phenotype and responses to coordinate tissue functions. ECM molecules interact with each other creating a functional network that also involves cell–ECM interactions through cell surface receptors that are critical for proper cell and tissue functionality [22]. The importance of the ECM as a multitasking player is underlined by the fact that its perturbation is at the origin of many acquired and inherited human disorders [23,24].
The mechanisms of these ECM-driven diseases include absent factors, aberrant signaling, and disorganization of several structural components [22,25,26]. For instance, the development and progression of various disorders comprising OA, rheumatoid arthritis (RA), fibrotic conditions, and cancer are associated with abnormal ECM remodeling, which drives disease progression by activating specific cell surface receptors and downstream signaling cascades that regulate cell-matrix-interactions [22,27]. In addition, mutations in a plethora of ECM-related genes severely disturb tissue homeostasis causing genetic disorders with variable clinical phenotypes affecting nearly every organ system [23,24]. The molecularly defined forms of EDS, with their 20 ECM-related causal genes currently recognized, are examples of these types of multisystem disorder [1].

Based on our previous [3,4,5,31,32] and current findings, we believe that the driving force in the context of hEDS pathology is a synergistic interplay among ECM perturbation and myofibroblast differentiation. The presence of an unbalanced proteolytic activity in hEDS-CM was proved through the detection of distinct degradation fragments (fs) of COLLI (COLLI-fs), TNs (TNs-fs), and FN (FN-fs) in patients’ cell culture media. In joint inflammatory diseases (e.g., OA and RA), it is well documented that an excessive ECM proteolysis upon cellular stress or tissue injury generates ECM degradation products that act as damage-associated molecular pattern molecules or DAMPs (e.g., FN, tenascin C (TNC), proteoglycans) [33,34,35,36]. These danger molecules promote maladaptive responses by inducing the expression of proinflammatory mediators and cytokines, nitric oxide, along with proteinases (including MMPs) that in turn, degrade further ECM components, creating a degradative and inflammatory feedback loop [37,38,39,40,41]. For instance, high amounts of FN-fs have been detected in cartilage and synovial fluid of OA patients and in vitro stimulations of human articular chondrocytes and synovial fibroblasts with FN-fs recapitulate several features of the pathological phenotype [39,42,43,44]. Similarly, TNC-fs act as endogenous inducers of cartilage ECM degradation by stimulating cytokines and MMPs production through binding with toll-like receptor 4 and integrins including αvβ3 [45,46]. Likewise, degradation products of COLLs alter the cartilage ECM turnover by promoting a catabolic state with the activation of proinflammatory mediators and MMPs [47,48,49].

The pivotal role of MMPs as crucial mediators of this vicious cycle was further emphasized by the results obtained treating patients’ cells with the doxy, an FDA-approved antibiotic acting as a nonselective MMP inhibitor. Doxy was able to restore in hEDS cells an appropriate ECM organization alongside a significant attenuation of myofibroblast-like phenotype. Interestingly, and contrary to the effects observed in control cells treated with hEDS-CM, in patients’ cells, doxy first induced the FN-ECM reorganization with concomitant almost complete αvβ3 integrin disappearance (at 2 days), followed by the TNs- and COLLI-ECM reestablishment (at 4 days), whereas for the partial α-SMA and Snail1/Slug disappearance respectively 6 and 8 days of treatment were required. Together, these findings corroborate the hypothesis that MMPs-mediated FN-ECM disorganization, activating an αvβ3 integrin-mediated signaling, is likely an important, but not the only, trigger underlying the hEDS pathogenesis, considering the incomplete myofibroblast dedifferentiation of hEDS cells in the presence of doxy.

Concerning MMPs, the finding that the degradative and differentiation potential of hEDS-CM on control fibroblasts is abolished by doxy further strengthens their pathophysiological impact, hence providing promising perspectives for preventing abnormal ECM remodeling and myofibroblast differentiation with a potential therapeutic translation for hEDS patients’ management. Doxy, acting via MMPs inhibition, immunomodulation, and nitric oxide synthase inhibition, has already provided encouraging results, in terms of biochemical and functional improvements including not only pain but also neuroinflammation-associated symptoms (e.g., anxiety and depression), in several human clinical trials for the treatment of OA and RA [21]. Likewise, clinical trials on X-fragile syndrome (FRAXA) with minocycline, another tetracycline derivative, has also shown to markedly ameliorate patients’ behavioral symptoms (e.g., anxiety, mood disorders, sleep disturbance, defects in memory consolidation) [58], many of which are also frequently observed in hEDS [2]. FRAXA is caused by the lack of the FMRP translational repressor that leads to the up-regulation of proteins implicated in synaptic transmission and plasticity including MMP9. The mode of action of minocycline in improving FRAXA neurological symptoms is clarified by its capability to reduce the levels of MMP9 [59]. Interestingly, the genetic interaction between MMP9 and FMRP also occurs in nonneuronal tissues, which might explain the nonneuronal symptoms of FRAXA patients, such as JHM, the hallmark characterizing hEDS, and some orthopedic features (e.g., flat foot and scoliosis).

Based on these observations in other human disorders with a perturbed ECM homeostasis associated with a pro-inflammatory state, in which MMPs inhibition has already demonstrated its efficiency in mitigating disease progression [21], we hypothesize that also in hEDS an MMPs-involving pathogenesis might explain several of the patients’ clinical signs and symptoms ranging from musculoskeletal complaints including pain to neurological issues. Although our promising findings were obtained in vitro and on a limited number of hEDS patients’ cells, we speculate that tetracyclines or other MMPs inhibitors could alleviate, at least in part, the complex patients’ clinical phenotype. However, prior to plan feasibility studies of MMPs inhibition in hEDS patients, thorough translational research is necessary to confirm the real implication of MMPs/TIMPs dysfunction, also considering the highly heterogeneous nature of the ECM composition which might be diversely perturbed at different body and organ sites. This mandatory in vivo research might eventually unravel one (or more than one) specific MMP as major disease driver(s) and could hence allow identifying more reliable compounds that may include the use of specific MMP inhibitors rather than a broad-spectrum approach which was the primary reason for adverse effects observed in some clinical trials [60].
In conclusion, the data presented here provide unprecedented evidence on a putative disease signature that may pave the way to the development of ECM-based targeted therapeutic strategies with a potential benefit for patients’ management.

 

[Fluffy]

Some people in this forum have benefited from low dose doxy. I have benefited enormously from the standard dose of 200 mg per day. I decided to take it around 10 years ago, motivated by research and also when a correspondent and one of the leading researchers of the "The Gulf War Syndrome" suggested that I take it to see if my symptoms improve.

Back then, I suspected that my problems were compounded by the vaccines I took as a requirement for University (medical school). By the time I was finished, I saw benefits in concentration, pain, energy levels, sleep, etc. Now I know that my extracellular matrix is particularly dysfunctional.

Here's more evidence that it prevents collagen degradation, particularly in those with a dysfunctional extracellular matrix:

https://www.mdpi.com/2073-4409/10/11/3236

Low dose is considered 50mg or less to have sub-microbial activity.

I was doing 20mg once a day with good results until a terrible flare up from stress caused me to halt everything out of confusion of what is and isn’t helping. I suspect that I’m intolerant of the capsules, I read that a lot of MCAS patients have gelatine and cellulose reactions.

I’m still in this flare and getting worse.

I’ll try 20mg x twice a day in powder form and report back in two weeks.

 

[nicklebleu]

I don’t think I am afflicted by hEDS.

I did a six-month doxy cycle about 10 years ago, too. While I didn’t have any major symptoms at the time, I did it mainly out of curiosity and bio-hacking. I don’t exactly remember the daily dose I took, from memory it was 100mg twice daily. There were no major changes either that were directly attributable to this cycle, but overall my health since then has been excellent.

I have changed quite a few things over the years, mostly in regards to nutrition and exercise, but looking back, this cycle may have had certain long-term benefits, even if there were no immediate drastic changes.

 

[Arwenn]

Low dose doxy is also used to treat dry eye from meibomian gland dysfunction and ocular rosacea (both inflammatory conditions), because of its anti-inflammatory effects on MMPs and other markers:

By inhibiting pro-inflammatory cytokines and enzymes such as IL-1β, TNF-α, and matrix metalloproteinases, doxycycline is a potent anti-inflammatory agent. Also, tetracyclines inhibit ocular flora lipase production, which lowers toxic byproducts such as free fatty acids. These features make tetracyclines useful in many ocular pathologies including chronic meibomian gland dysfunction, ocular rosacea, and recurrent corneal erosion.