Session Information
Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's - Pathogenesis, Animal Models and Genetics I
Session Type: Abstract Submissions (ACR)
Background/Purpose
The synthesis and degradation of extracellular matrix (ECM), particularly collagen, is one of the central mechanisms perturbed in scleroderma (SSc). Understanding the kinetics of this process can be of great value to define disease activity during the course of SSc and to develop better tools to assess with precision response to therapeutic interventions.
Methods
Using a stable isotope (deuterium) labeling method and a new kinetic proteomic approach designed to enrich for ECM, we assessed the turnover of collagen in the skin of SSc subjects. Moreover, we pursued the extraction of different collagen pools based on their solubility to measure kinetics of collagen subtypes and other matrix molecules. Three subpopulations were studied: limited (n=6), diffuse early-active (n=5) and diffuse late-stage SSc (n=6). Subjects were given heavy water for 3 weeks prior to a skin biopsy. Protein, lipid and cell kinetics were measured and correlated to gene array and histology from adjacent biopsies.
Results
Total collagen synthesis rates (% new collagen after 3 weeks of labeling) were significantly higher in late-stage diffuse SSc subjects (5.052%±1.953) compared to early-active (1.986%±0.8226; p=0.0031) or normal subjects (2.237%±0.6365; p=0.0031) demonstrating that fibrotic tissue in these subjects undergoes active remodeling. The microarray data showed that the higher collagen synthesis detected in late diffused patients is significantly associated with the expression of genes involved with fibrosis and cell cycle. When compared to total collagen synthesis rates, kinetic analysis of individual collagen pools revealed that the guanidine soluble collagen (corresponding to recently synthetized uncross-linked collagen and immature matrix) represented a greater proportion of the total collagen pool in the late diffuse subjects that have more established fibrosis.
Conclusion
This study shows that cutaneous fibrosis in late-stage SSc is not a static hypodynamic scarring but rather undergoes active remodeling with a pool of newly synthesized, uncross-linked collagen. These data emphasize that the biological processes and pathogenetic networks driving SSc skin involvement likely change over time with the different stages of the disease.
Disclosure:
C. Emson,
Kinemed,
3;
M. Decaris,
Kinemed,
3;
M. Gatmaitan,
Kinemed,
3;
F. Luo,
Kinemed,
3;
D. Holochwost,
Kinemed,
3;
S. FloraCruz,
Kinemed,
3;
T. Angel,
Kinemed,
3;
K. Li,
Kinemed,
3;
M. Hellerstein,
Kinemed,
3;
F. M. Wigley,
None;
S. Turner,
Kinemed,
3;
F. Boin,
None.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/skin-collagen-synthesis-rates-distinguish-between-early-and-late-diffuse-scleroderma-patients/