The DOI matches its Crossref record; 57 of the 58 references it cites were found in a registry or an index.
Pain-related behaviors and abnormal cutaneous innervation in a murine model of classical Ehlers-Danlos syndrome
Open accessAbstract
Classical Ehlers–Danlos syndrome (cEDS) is a connective tissue disorder caused by heterozygous mutations in one of the type V collagen-encoding genes,COL5A1 or COL5A2. cEDS is characterized by generalized joint hypermobility and instability, hyperextensible, fragile skin, and delayed wound healing. Chronic pain is a major problem in cEDS patients, but the underlying mechanisms are largely unknown, and studies in animal models are lacking. Therefore, we assessed pain-related behaviors in haploinsufficient Col5a1+/−mice, which clinically mimic human cEDS. Compared to wild-type (WT) littermates, 15 to 20-week-old Col5a1+/−mice of both sexes showed significant hypersensitivity to mechanical stimuli in the hind paws and the abdominal area, but responses to thermal stimuli were unaltered. Spontaneous behaviors, including distance travelled and rearing, were grossly normal in male Col5a1+/−mice, whereas female Col5a1+/−mice showed altered climbing behavior. Finally, male and female Col5a1+/−mice vocalized more than WT littermates when scruffed. Decreased grip strength was also noted. In view of the observed pain phenotype,Col5a1+/−mice were crossed with Na V 1.8-tdTomato reporter mice, enabling visualization of nociceptors in the glabrous skin of the footpad. We observed a significant decrease in intraepidermal nerve fiber density, with fewer nerves crossing the epidermis, and a decreased total nerve length of Col5a1+/−mice compared to WT. In summary, male and female Col5a1+/−mice show hypersensitivity to mechanical stimuli, indicative of generalized sensitization of the nervous system, in conjunction with an aberrant organization of cutaneous nociceptors. Therefore,Col5a1+/−mice will provide a useful tool to study mechanisms of pain associated with cEDS.
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“The exact same features are found in a mouse model of classic EDS (cEDS) (Col5a1+/−), including allodynia and hyperalgesia, as well as the denervation of small C-fibers seen in the human condition [98].”
From The Relationship between Autism and Ehlers-Danlos Syndromes/Hypermobility Spectrum Disorders (2020) · cites this paper as [98]
In the citing paper
“Although the mechanism is not well understood, it is clear that connective tissue dysfunction lies upstream of such peripheral neuropathies.”
From The Relationship between Autism and Ehlers-Danlos Syndromes/Hypermobility Spectrum Disorders (2020) · cites this paper as [98]
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Malfait, F., Francomano, C., Byers, P., Belmont, J., Berglund, B., Black, J., Bloom, L., Bowen, J. M., Brady, A. F., Burrows, N. P., et al. (2017) · American Journal of Medical Genetics Part C: Seminars in Medical Genetics · doi:10.1002/ajmg.c.31552 · Cited by 1,936 · cited 2×
“com/PAIN/B55).(20) The syndromic presentation of joint hypermobility, skin hyperextensibility, abnormal scar formation, and easy bruising is key to diagnosis, but awide range of other systemicmanifestations can be present.”
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The Relationship between Autism and Ehlers-Danlos Syndromes/Hypermobility Spectrum Disorders
Casanova, E. L., Baeza-Velasco, C., Buchanan, C. B., & Casanova, M. F. (2020) · Journal of Personalized Medicine · doi:10.3390/jpm10040260 · Cited by 109
Geraghty, T., Obeidat, A. M., Ishihara, S., Wood, M. J., Li, J., Lopes, E. B. P., Scanzello, C. R., Griffin, T. M., Malfait, A., & Miller, R. E. (2023) · Arthritis & Rheumatology · doi:10.1002/art.42530 · Cited by 57
Self-citationPain in the Ehlers–Danlos syndromes: Mechanisms, models, and challenges
Malfait, F., Colman, M., Vroman, R., De Wandele, I., Rombaut, L., Miller, R. E., Malfait, A., & Syx, D. (2021) · American Journal of Medical Genetics Part C: Seminars in Medical Genetics · doi:10.1002/ajmg.c.31950 · Cited by 41
Self-citationThe Role of Transforming Growth Factor-β Signaling in Myxomatous Mitral Valve Degeneration
Tang, Q., McNair, A. J., Phadwal, K., MacRae, V. E., & CORCORAN, B. M. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.872288 · Cited by 31
Lai, A., Iliff, D., Zaheer, K., Wang, D., Gansau, J., Laudier, D. M., Zachariou, V., & Iatridis, J. C. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24043425 · Cited by 21
Metadata
- Authors
- Syx, D., Miller, R. E., Obeidat, A. M., Tran, P. B., Vroman, R., Malfait, Z., Miller, R. J., Malfait, F., & Malfait, A.-M.
- Affiliations
- Rush University Medical Center (US)
- Northwestern University (US)
- Ghent University (BE)
- Corresponding author
- Malfait, Anne-Marie
- ORCID
- Venue
- Pain
- Published
- 2020-05-29
- Volume
- 161
- Issue
- 10
- Pages
- 2274-2283
- ISSN
- 0304-3959 (ISSN-L)
- 1872-6623
- PMC
- PMC7967806
- OpenAlex
- W3029033779
- Cited by
- 19
- References
- 58
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 5 · 2022: 3 · 2021: 3 · 2020: 2
- FWCI
- 1.96
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Pain (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion, other-oa)
- Funders
- Rush University
- Fonds Wetenschappelijk Onderzoek (12Q5917N, 3G041519, 1842318N)
- Universiteit Gent (BOFMET2015000401)
- Vlaamse regering
- National Institutes of Health
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (K01AR070328, T32AR073157, R01AR064251, R01AR060364)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Keywords
- classical Ehlers-Danlos syndrome, COL5A1, type V collagen, chronic pain, mechanical hypersensitivity, thermal sensitivity, nociceptors, intraepidermal nerve fibers, skin innervation, sex differences, vocalizations, grip strength, connective tissue diseases
- MeSH terms
- Animals, Disease Models, Animal, Ehlers-Danlos Syndrome, Female, Male, Mutation, Pain, Skin, Collagen Type V, Mice
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