Endoglin haploinsufficiency is associated with differential regulation of extracellular matrix production during skin fibrosis and cartilage repair in mice
Transforming growth factor (TGF)-β is a multifunctional growth factor with potent pro-fibrotic effects. Endoglin is a TGF-β co-receptor that strongly regulates TGF-β signaling in a variety of cell types. Although aberrant regulation of TGF-β signaling is known to play a key role in fibrotic diseases such as scleroderma and impaired cartilage repair, the significance of endoglin function in regulating these processes is poorly understood. Here we examined whether endoglin haploinsufficiency regulates extracellular (ECM) protein expression and fibrotic responses during bleomycin induced skin fibrosis and surgically induced osteoarthritis, using endoglin-heterozygous (Eng+/−) mice and wild-type (Eng+/+) littermates. Skin fibrosis was induced by injecting mice intradermally with bleomycin or vehicle. Osteoarthritis was induced surgically by destabilization of medial meniscus. Dermal thickness, cartilage integrity and ECM protein expression were then determined. Eng+/− mice subjected to bleomycin challenge show a marked decrease in dermal thickness (P < 0.005) and reduced collagen content and decreased collagen I, fibronectin, alpha-smooth muscle actin levels as compared to Eng+/+ mice, both under basal and bleomycin treated conditions. Eng+/− mice undergoing surgically induced osteoarthritis show no differences in the degree of cartilage degradation, as compared to Eng+/+ mice, although chondrocytes isolated from Eng+/− display markedly enhanced collagen II levels. Our findings suggest that endoglin haploinsufficiency in mice ameliorates bleomycin-induced skin fibrosis suggesting that endoglin represents a pro-fibrotic factor in the mouse skin. However, endoglin haploinsufficiency does not protect these mice from surgically indiced cartilage degradation, demonstrating differential regulation of endoglin action during skin and cartilage repair.
KeywordsFibrosis, skin, cartilage, osteoarthritis Endoglin TGF-beta Scleroderma Systemic sclerosis Animal model
This study was supported by a Canadian Institutes of Health Research (CIHR) operating grant (FRN13732) to AP, a Research Award to AA from the King AbdulAziz University, Jeddah, Saudi Arabia, and a PhD studentship award to YC from FRQS, Quebec.
Compliance with Ethical Standards
Conflicts of Interest
The authors have no conflicts of interest.
- Denton CP (2015) Systemic sclerosis: from pathogenesis to targeted therapy. Clin Exp Rheumatol 33(4 Suppl 92):S3–S7Google Scholar
- Finnson KW, Parker WL, Chi Y, Hoemann C, Goldring MB, Antoniou J, Philip A (2010) Endoglin differentially regulates TGF-β-induced Smad2/3 and Smad1/5 signalling and its expression correlates with extracellular matrix production and cellular differentiation state in human chondrocytes. Osteoarthr Cartil 18:1518–1527CrossRefPubMedGoogle Scholar
- Heldin CH, Moustakas A (2016) Signaling receptors for TGF-β family members. Cold Spring Harb Perspect Biol 8. https://doi.org/10.1101/cshperspect.a022053
- Leask A, Abraham DJ, Finlay DR, Holmes A, Pennington D, Shi-Wen X, Chen Y, Venstrom K, Dou X, Ponticos M, Black C, Bernabeu C, Jackman JK, Findell PR, Connolly MK (2002) Dysregulation of transforming growth factor β signaling in scleroderma: overexpression of endoglin in cutaneous scleroderma fibroblasts. Arthritis Rheum 46:1857–1865CrossRefPubMedGoogle Scholar
- Minamisawa S, Gu Y, Ross J Jr, Chien KR, Chen J (1999) A post-transcriptional compensatory pathway in heterozygous ventricular myosin light chain 2-deficient mice results in lack of gene dosage effect during normal cardiac growth or hypertrophy. J Biol Chem 274:10066–10070CrossRefPubMedGoogle Scholar
- Monemdjou R, Vasheghani F, Fahmi H, Perez G, Blati M, Taniguchi N, Lotz M, St-Arnaud R, Pelletier JP, Martel-Pelletier J, Beier F, Kapoor M (2012) Association of cartilage-specific deletion of peroxisome proliferator-activated receptor gamma with abnormal endochondral ossification and impaired cartilage growth and development in a murine model. Arthritis Rheum 64:1551–1561CrossRefPubMedPubMedCentralGoogle Scholar
- Morikawa M, Derynck R, Miyazono K (2016) TGF-β and the TGF-β family: context-dependent roles in cell and tissue physiology. Cold Spring Harb Perspect Biol 8Google Scholar
- Trackman PC (2017) Functional importance of lysyl oxidase family propeptide regions. J Cell Commun Signal. https://doi.org/10.1007/s12079-017-0424-4
- Truett GE, Heeger P, Mynatt RL, Truett AA, Walker JA, Warman ML (2000) Preparation of PCR-quality mouse genomic DNA with hot sodium hydroxide and tris (HotSHOT). BioTechniques 29(52):54Google Scholar
- Vorstenbosch J, Gallant-Behm C, Trzeciak A, Roy S, Mustoe T, Philip A (2013b) Transgenic mice overexpressing CD109 in the epidermis display decreased inflammation and granulation tissue and improved collagen architecture during wound healing. Wound Repair Regen 21:235–246CrossRefPubMedGoogle Scholar