Possible Non-Genetic causes for hEDS/HSD MASTERPOST
Ehlers Danlos Syndrome currently has 14 subtypes, and 13 of those have genetic variants identified. hEDS, however, does not. hEDS is by far the most common form of EDS, and it's presentation is quite heterogeneous. So, while most folks realize that there are probably multiple genes causing the different presentations of hEDS, what fewer people realize is that a number of doctors, researchers, and patients also believe that there are some very possible non-genetic factors that may be behind many instances of hEDS/HSD as well.
This continually-in-progress master post will be where I collect peer-reviewed articles on this subject as I come across them. I haven't taken a deep-dive into the research to try to find everything out there, so this is absolutely NOT a list of everything that exists, and please do leave a comment to share any relevant articles you know about!- Catabolism of Intact Type VI Collagen Microfibrils: Susceptibility to Degradation by Serine Proteinases (1993) (PDF Link)
"We report that intact type VI collagen is catabolized by the serine proteases but is resistant to degradation by the metalloproteinases. This is the first indication of intact type VI collagen degradation and implicates cells which are major components of the inflammatory response."
We present the first direct biochemical evidence for the turnover of intact type VI collagen microfibrils. Matrix-degrading enzymes of the serine proteinase class, including rat mast cell chymases I and II, human mast cell tryptase, neutrophil elastase, cathepsin G and trypsin, were able to catabolize intact type VI collagen microfibrils isolated from foetal bovine skin and metabolically labelled intact type VI collagen immunoprecipitated from fibroblast culture medium. By contrast, intact type VI collagen was not degraded by the human matrix metalloproteinases, MMP-1, MMP-2, MMP-3 and MMP-9. These data have important implications for the stability of type VI collagen in connective tissues and highlight the potential role of serine proteinases both in normal type VI collagen turnover and in inflammatory conditions characterized by matrix degradation.
► "Type VI collagen has recently been shown to interact in vitro with several key elements of matric, including hyaluronan (3, 4, 5), type I collagen (6) and decorin (7), and with cells (8-10). From this information, it has been proposed that the prime function of type VI collagen is to link the major elements of the extracellular matrix (2, 6)."
► "Connective tissue cells synthesize and secrete a group of matrix metalloproteinases which can synergistically digest major macromolecules such as fibrillar collagens (types I, II, and III), non-fibrillar collagens (types IV, VII, VIII, and X) and the FACIT collagens which coat collagen fibril bundles (13-15). The interstitial and neutrophil collagenases (MMPs - 1 and -5) are capable of cleavage at specific sites across the triple helix, producing denatured fragments susceptible to degradation by other proteases including gelatinases (MMPs -2 and -9) and stromelysin (MMPs -2 and -10). Granulocytes such as mast cells and neutrophils mainly secrete serine proteinass which may attack a wide range of protein substrates and may also contribute to the processing of denatured collagens (13)."" ► "Thus, catabolism of type VI collagen may be a feature of early inflammatory lesions which may conotribute to the accelerated breakdown of connective tissue associated with certain pathological conditions." ► "Matrix turnover is generally a slow and carefully regulated process in structures such as adult tendon and skin. However, in some physiological conditions such as bone remodelling, wound healing, mammary gland and uterine involution, and maturation of endometrium, matrix breakdown and regeneration occur more rapidly and can be associated with degradation and synthesis of type VI collagen (25, 26). A high turnover of connective tissue components is also a feature of inflammatory infiltrates where the increased presence of neutrophils, macrophages, and mast cells are associated not only with recruitment of reparative cells but in particular the degradation of structural elements. In early inflammatory lesions, therefore, the opportunity exists for an initial stage of type VI collagen catabolism which may in turn facilitate the accelerated breakdown of other connective tissue components in a variety of pathological conditions." - Human Mast Cell β-Tryptase Is a Gelatinase (2003)
"Considering the location of mast cells in connective tissues< and the recently recognized role of mast cells in disorders in which connective tissue degradation is a key event, e.g., rheumatoid arthritis, it is thus likely that tryptase may contribute to extracellular matrix-degrading processes in vivo."
Remodeling of extracellular matrix is an important component in a variety of inflammatory disorders as well as in normal physiological processes such as wound healing and angiogenesis. Previous investigations have identified the various matrix metalloproteases, e.g., gelatinases A and B, as key players in the degradation of extracellular matrix under such conditions. Here we show that an additional enzyme, human mast cell beta-tryptase, has potent gelatin-degrading properties, indicating a potential contribution of this protease to matrix degradation. Human beta-tryptase was shown to degrade gelatin both in solution and during gelatin zymographic analysis. Further, beta-tryptase was shown to degrade partially denatured collagen type I. beta-Tryptase bound strongly to gelatin, forming high molecular weight complexes that were stable during SDS-PAGE. Mast cells store large amounts of preformed, active tryptase in their secretory granules. Considering the location of mast cells in connective tissues and the recently recognized role of mast cells in disorders in which connective tissue degradation is a key event, e.g., rheumatoid arthritis, it is thus likely that tryptase may contribute to extracellular matrix-degrading processes in vivo.
► "Here we show that an additional enzyme, human mast cell β-tryptase, has potent gelatin-degrading properties, indicating a potential contribution of this protease to matrix degradation. Human β-tryptase was shown to degrade gelatin both in solution and during gelatin zymographic analysis. Further, β-tryptase was shown to degrade partially denatured collagen type I."
► "Tissue-remodeling processes take place in many physiological and pathological conditions, e.g., embryonic development, wound healing, rheumatoid arthritis, and tumor invasion. In these processes degradation of the extracellular matrix (ECM)3 is required to allow the proliferation and/or migration of different cell types." ► "At present, matrix metalloproteinases (MMPs) are being recognized as the main players in the ECM degradation associated with various tissue-remodeling processes. [...] Together the MMPs have the ability to degrade all the different types of macromolecules present in the extracellular matrix, e.g., collagens, laminin, fibronectin, and proteoglycans." ► "Mast cells synthesize and store large amounts of various serine proteases of two subclasses: tryptases and chymases. In connective tissue-type mast cells, both the chymases and tryptases are packaged in the secretory granules in tight complexes with heparin proteoglycan (8). When mast cells are activated [...] the mast cells degranulate and release large amounts of serine proteases and other inflammatory mediators, e.g., histamine and TNF-α (9)." ► "The large amounts of proteases that are being released by mast cells during inflammatory conditions together with the fact that the mast cell serine proteases are stored and released in their active form make these proteases likely candidates for involvement in connective tissue degradation. Indeed, it has been indicated previously that mast cell chymase may promote ECM degradation by processing proMMP-9 (pro-gelatinase B) to its active form (10, 11) and by directly degrading various connective tissue components, e.g., fibronectin (12)." ►"No detectable degradation was observed for type I collagen when incubations were performed at room temperature (not shown). In contrast, when incubations were conducted at 37°C [98.6°F], a marked degradation of type I collagen was observed at pH 6.0... and, to a lesser extent, at pH 7.5 (not shown). The degradation of type I collagen at 37°C, but not at room temperature, suggests that the elevated temperature causes partial unfolding of the collagen into a form that is susceptible to degradation by tryptase. This is in agreement with earlier reports that demonstrated denaturation of intact type I collagen at temperatures >36°C [96.8°F] (28, 29). Moreover, control experiments showed that the type I collagen preparation was susceptible to degradation (at 37°C) by pancreatic trypsin, an enzyme that is not recognized as a collagenase (not shown). These results indicate that β-tryptase appears to have the ability to degrade partially denatured, but not native, type I collagen." ► "However, our results indicate that denatured collagen, obtained after unfolding of the triple helix, readily enters the central pore of tetrameric tryptase. It is important to note that the active tryptase monomers, similarly to the tetramers, were not able to degrade intact collagen type I. This indicates that the failure of tetrameric β-tryptase to degrade intact collagen may not only be a result of the restricted accessibility to its active sites, but may also be due to an absolute requirement for collagen unfolding to unmask susceptible peptide bonds." ► "The present findings are thus in agreement with the well-established idea that only the collagenases, i.e., interstitial collagenase, neutrophil collagenase, collagenase-3, and cathepsin K, are able to destroy the highly ordered structure of fibrillar collagens, and that subsequent degradation is conducted by other proteases (2, 5) (41)." ► "We may thus propose that mast cell β-tryptase could act in a similar fashion as the previously described gelatinases (e.g., MMP-2 and -9), i.e., once collagen strands are disordered, tryptase would be able to continue the degradation process. Importantly, mast cells reside in the connective tissue and contain large stores of preformed active tryptase that, once released, could act early in the ECM degradation process." ► "Hence, degradation of ECM by tryptase may be a comparably long-lived event following mast cell degranulation, insensitive to, e.g., the protease inhibitors that escape into the tissue due to the plasma leakage that occurs during an inflammatory process." ► "Heparin, the physiological ligand to tryptase in the secretory granule (9), is a well-known stabilizing agent for tryptase and has also been implicated in the assembly of the tryptase tetramer (45). The interaction of tryptase with heparin is promoted by the low pH that is present in the secretory granules (∼5.5), and it is thought that exocytosed tryptase is regulated by its dissociation from heparin due to a higher extracellular pH, leading to tryptase monomerization. The released monomers will rapidly lose activity, although it is possible that they may possess enzymatic activity for a short time period (23). If, however, the monomers are rescued by binding to heparin, they will regain enzymatic activity (46, 47), predominantly by the generation of active tryptase monomers (23)." ► "According to the results presented here, tryptase may thus, after dissociation from heparin, interact strongly with collagens (or proteoglycans) in the ECM. A strong binding of tryptase to ECM is also supported by a previous study in which human lung tryptase was found to bind to bovine cartilage (47). This interaction could serve to target tryptase to its potential substrate in the ECM." - Mast cell tryptase and photoaging: possible involvement in the degradation of extra cellular matrix and basement membrane proteins (2007) (PDF Link)
"Our studies of substrate-embedded zymography indicated the possibility of direct cleavage of collagen type IV and I by tryptase and results showed two possibilities of contribution of mast cell tryptase to ECM degradation (Fig. 7). First, tryptase may activate the latent ECM-degrading proteases to their active forms and degrade the ECM components. Secondly, tryptase may degrade directly of ECM components."
Mast cells are widely distributed in the connective tissue of the body, but are particularly prominent in tissues such as skin. An increased number of mast cells can be found in the dermis under inflammatory conditions and ultraviolet (UV) exposed skin. Previous investigations have identified matrix metalloproteinases (MMPs) as key enzymes in the degradation of extra cellular matrix (ECM). This study reports about the potential contribution of human mast cell tryptase as a new triggering enzyme in matrix degradation process. Recent studies suggest that mast cell-derived proteases can activate MMPs. We investigated both the degradation of cellular matrix components and activation of MMPs by human tryptase. Mast cells are increased in photoaged skin and the increase of mast cell tryptase in UV irradiated skin was confirmed. Human mast cell tryptase was purified from human tonsils by a series of standard chromatographic procedures. Degradation of collagen type I was achieved by incubation of human type I collagen with tryptase and the fragments were quantified by SDS-PAGE and staining with Coomassie Brilliant Blue 250-R (CBB). Treatment with tryptase resulted in the activation of proMMP-9 as revealed by gelatinolytic activity in type IV collagen zymography. When tryptase was incubated with human type IV collagen, gradual degradation of intact collagen was detected by Western blotting. Furthermore, type IV collagen degradation was observed in the basement membrane (BM) of a three-dimensional (3D) skin model. Degranulation of mast cells, which release tryptase, can activate MMPs and causes direct damage to ECM proteins. These findings strongly implicate that tryptase either alone or in conjunction with activation of MMPs, can participate in ECM damage and the possible destruction of BM leading to photoaging.
► "When tryptase was incubated with human type IV collagen, gradual degradation of intact collagen was detected by Western blotting."
► "Furthermore, type IV collagen degradation was observed in the basement membrane (BM) of a three-dimensional (3D) skin model. Degranulation of mast cells, which release tryptase, can activate MMPs and causes direct damage to ECM [extra-cellular matrix] proteins." ► "Further, recent data indicates that mast cell tryptase is gelatinase, similar to MMP-2 or MMP-9, and has potent gelatin degrading properties [5, 24]." ► "Evidence is also emerging that mast cell tryptase is involved in focal dermal–epidermal separation through the cleavage of Wbronectin, an important adhesive protein in the ECM, as well as an abrupt decrease in keratinocyte adhesion in skin [17]." ► "Tryptase also activates proteinase activated receptor-2 (PAR-2) and regulates the inflammatory process [4, 32]. Therefore, the mast cell tryptase being released in its active form makes it a possible candidate for involvement in ECM degradation by processing proMMPs to active forms or direct damage to ECM proteins." ► "Treatment of collagen type I with tryptase resulted in degradation of the intact collagen to produce a visible fragment (Fig. 3). However, no detectable fragmentation was observed after pre-incubation of tryptase with leupetin, a known inhibitor of tryptase." ► "Type IV collagen was cleaved to two fragments after incubation with tryptase, and it was further degraded to several fragments by proMMP-9 that was pre-incubated with mast cell tryptase (Fig. 5). Activation of proMMP-9 by tryptase enhanced fragmentation of type IV collagen, indicating that tryptase together with MMP-9 could lead to further degradation of type IV collagen." ► "Immunoflouorescence staining of 3D skin sections clearly demonstrated that the incubation with tryptase for 6 h resulted in the degradation of collagen type IV layer at the BM area compared to control skin section (Fig. 6)." ► "Mast cell granules contain several mediators (TNF-alpha, prostaglandin E, and serine proteinases) that could directly or indirectly modulate the degradation of ECM or activate the proenzyme form of MMPs [2, 17, 24]." ► "Previous studies have suggested that mast cell tryptase may be involved in dermo-epidermal separation and the activation of proMMP-3 and 72 kDa gelatinase [5, 21, 24, 34]. Earlier studies suggested that activation of proMMP-3 resulting in activation of proMMP-1 lead to degradation of ECM protein such as collagen type I [34]. However, Hallgren et al. recently reported that the addition of tryptase to human endothelial cell in culture resulted in direct activation of MMP-1 [7]." ► "The MMPs are considered as an important enzyme for the degradation of connective tissues in both physiological and pathological situations. In this study, we found that tryptase can activate proMMP-9 (92 kDa gelatinase) and cleave collagen type IV, the most important BM protein. These findings indicate that an increase in mast cells in inflammatory process induced by chronic UV exposure could damage the BM." ► "In conclusion, mast cell tryptase either alone, or in conjunction with activation of metalloproteinases, can participate in ECM damage and the possible destruction of BM. Therefore, tryptase could be a promising target for the treatment of ECM degradation and photoaging [26, 31, 35, 36]." - Rheumatological presentation of Bartonella koehlerae and Bartonella henselae bacteremias (2018)
"In addition to reporting fatigue, muscle pain and joint pain, the veterinarian in this case report experienced a progressive increase in joint laxity resulting in a diagnosis at 2 major medical centers of hypermobile Ehlers–Danlos syndrome (EDS type III). Recent research supports a potential role for mast cell activation and dysregulation in a subset of nongenetically mediated EDS patients with joint hypermobility syndrome.[6] In addition to the lung and gastrointestinal tract, mast cells are prevalent in cutaneous tissues throughout the body.[6] In the context of a plausible pathogenesis, a long-standing Bartonella spp. infection, accompanied by chronic mast cell activation could potentially contribute to ongoing damage to connective tissues; thereby resulting in clinical findings indicative of EDS."
Introduction: Systemic Bartonella spp. infections are being increasingly reported in association with complex medical presentations. Individuals with frequent arthropod exposures or animal contact appear to be at risk for acquiring long standing infections with Bartonella spp.
Case report: This case report describes infections with Bartonella koehlerae and Bartonella henselae in a female veterinarian whose symptoms were predominantly rheumatologic in nature. Infection was confirmed by serology, polymerase chain reaction (PCR), enrichment blood culture, and DNA sequencing of amplified B koehlerae and B henselae DNA. Long-term medical management with antibiotics was required to achieve elimination of these infections and was accompanied by resolution of the patient's symptoms. Interestingly, the patient experienced substantial improvement in the acquired joint hypermobility mimicking Ehlers–Danlos Syndrome (EDS) type III. Conclusion: To facilitate early and directed medical interventions, systemic bartonellosis should potentially be considered as a differential diagnosis in patients with incalcitrant rheumatological symptoms and frequent arthropod exposures or extensive animal contact.► "In 2010, a 31-year-old female veterinarian with a progressive, 2-year history of rheumatologic and orthopedic symptoms elected to enter a Bartonella research study [...]. Recent evaluations by rheumatologists and EDS experts at Harvard and Johns Hopkins Hospitals reported that the patient met criteria for EDS, hypermobility type III. Genetic testing was not performed (as there is no genetic lesion known presently to be associated with EDS type III)."
► "At the time of study entry, the veterinarian was no longer able to perform daily living or employment activities. Symptoms reported on the study questionnaire included generalized muscle/ joint pain, muscle weakness, headaches, tingling, and fatigue. In 2009, the previously healed sesamoid bone re-fractured and had not re-healed. Newly noted joint hypermobility had progressively worsened (Beighton score 7/9), and the woman experienced multiple joint subluxations daily. Breast" ► "Based on the positive B koehlerae PCR and because veterinarians are occupationally at-risk for acquiring B koehlerae infections,[1–3] she was treated with azithromycin, rifampin, and minocycline. Four weeks after starting antibiotics, joint pain was decreased. By August 2010, joint hypermobility had resolved (Beighton score 0/9) and the sesamoid bone had united. Retesting in September 2010 confirmed B koehlerae-specific seroconversion withnocross-reactivity to the otherBartonella spp.antigens." ► "In this patient, clinical, microbiological and therapeutic results suggest that Bartonella spp. may play a role in the pathogenesis of joint hypermobility. In addition to reporting fatigue, muscle pain and joint pain, the veterinarian in this case report experienced a progressive increase in joint laxity resulting in a diagnosis at 2 major medical centers of hypermobile Ehlers–Danlos syndrome (EDS type III)." ► "Recent research supports a potential role for mast cell activation and dysregulation in a subset of nongenetically mediated EDS patients with joint hypermobility syndrome.[6] In addition to the lung and gastrointestinal tract, mast cells are prevalent in cutaneous tissues throughout the body.[6] In the context of a plausible pathogenesis, a long-standing Bartonella spp. infection, accompanied by chronic mast cell activation could potentially contribute to ongoing damage to connective tissues; thereby resulting in clinical findings indicative of EDS." ► "Research is needed to determine the extent to which Bartonella spp. may colonize collagen and/or bone and if persistent infection and inflammation can contribute to the pathogenesis of hypermobili- ty (EDS) that may include progressive joint pain, tendinosis, and meniscal instability."
