Systemic scleroderma involves fibrosis of the skin and internal organs, but its etiology is poorly understood and it has no known genetic causes-factors that have hampered the development of models and, in turn, therapies.

Now, a North American team has shown that mice harboring a mutant form of the glycoprotein fibrillin 1 (Fbn1) recapitulated skin fibrosis and other symptoms seen in patients with systemic scleroderma.1 Although the team showed the therapeutic effect of targeting different proteins whose expression was altered by the mutant glycoprotein, future studies will have to zero in on the best target for treating scleroderma in patients.

FBN1, a glycoprotein secreted by fibroblasts into the extracellular matrix, is an essential component of the microfibrils found in many types of connective tissue. FBN1 also interacts with integrins expressed on other cell types, such as dermal-infiltrating dendritic cells (DCs), to regulate adhesion.

FBN1 mutations can cause a number of different conditions and diseases that affect connective tissue, most notably Marfan syndrome.2

In 2006, a team at The Johns Hopkins University led by Harry Dietz showed that some FBN1 mutations could upregulate signaling by transforming growth factor-b (TGFB; TGFb)-a family of cytokines that is involved in the proliferation and differentiation of most cells-to cause aortic aneurysms that occur in some patients with Marfan syndrome.3

Dietz's team also identified a few patients harboring FBN1 mutations who exhibited symptoms of both Marfan syndrome and stiff skin syndrome, a rare inherited form of skin fibrosis with only about 40 cases reported in the literature. Subsequently, another Dietz-led team determined that stiff skin syndrome was caused by mutations in the integrin-binding domain of FBN1 and involved upregulation of TGFb signaling.4

Now, his newest team has hypothesized that mice with loss-of-function mutations in the integrin-binding domain of Fbn1 might provide insights into the pathobiology of another fibrotic disease associated with increased TGFb signaling-scleroderma.5

Indeed, the team found that the Fbn1-mutant mice exhibited skin fibrosis, high levels of collagen in the skin and the high levels of anti-nuclear and anti-topoisomerase I (Top1) antibodies in circulation seen in patients with systemic scleroderma.

Plasmacytoid DCs isolated from the dermis of the mutant mice and fibroblasts from patients with systemic scleroderma had high surface levels of integrin b1 (CD29) and activated integrin b3 (GPIIIa; CD61).

In the Fbn1-mutant mice, a mouse Cd29-activating antibody-which mimicked Fbn1's interactions with Cd29-decreased skin fibrosis and levels of circulating anti-nuclear and anti-Top1 antibodies compared with an inactive murine control antibody.

Knockout of Cd61 or a pan-specific, anti-Tgfb antibody also decreased skin fibrosis in the mice compared with normal Cd61 expression or a control antibody.

In the patient fibroblasts, a CD29-activating antibody, an anti-CD61 antibody or a small molecule against type I TGFb receptor decreased collagen expression compared with inactive control antibodies.

Additionally, patient fibroblasts and DCs from the dermis of the mouse models had elevated TGFb-dependent MAP kinase 3 (MAPK3; ERK-1) and/or MAPK1 (ERK-2) signaling. In the fibroblasts and models, a small molecule MEK inhibitor decreased collagen expression and skin fibrosis, respectively, compared with vehicle.

Collectively, the findings suggest that stiff skin syndrome and systemic scleroderma involve similar pathological mechanisms (see "Restoring dermal integrity") and thus could potentially be treated with the same therapeutic strategies, the team wrote in its report in Nature.

There are no drugs approved to treat stiff skin syndrome or the underlying causes of systemic scleroderma. Therapies for the latter primarily involve topical or systemic immunosuppressive drugs to ameliorate symptoms.

Dietz is a professor of pediatrics, medicine, and molecular biology and genetics at The Johns Hopkins University School of Medicine and a professor of medicine and genetics at the school's McKusick-Nathans Institute for Genetic Medicine. He is also director of the school's William S. Smilow Center for Marfan Syndrome Research and an investigator at the Howard Hughes Medical Institute. His team included a researcher from McGill University.

Although stiff skin syndrome and scleroderma have differing or unknown causes, "Dietz has shown that, once initiated, the diseases appear to have similar biological processes that converge on the same pathways," Luke Evnin, chairman of the Scleroderma Research Foundation, told SciBX. "These mouse models could help us study the biology behind scleroderma and identify therapeutic strategies for preventing or reversing skin fibrosis."

Evnin, who is a managing director at life sciences VC MPM Capital, said that the Scleroderma Research Foundation recruited Dietz about six years ago to work on scleroderma and funded the research in the Nature study.

"Among the obstacles to understanding scleroderma are the heterogeneity of the disease-systemic sclerosis that affects multiple organs-and the variability of its clinical course. The Nature study helps reduce this complexity by focusing on a genetic model involving only pathological fibrosis of the skin," said Gary Nabel, CSO of Sanofi.

Thus, this high-fidelity model of skin scleroderma could be used to screen for new compounds to treat the disease or possibly repurpose those in development for other diseases, he said.

Sanofi's SAR100842, an antagonist of lysophosphatidic acid receptor 1 (LPAR1; EDG2; LPA1) and LPAR3 (EDG7; LPA3), is in Phase II testing to treat scleroderma. LPA antagonists are thought to modify TGFb activity indirectly, Nabel said.

Going more than skin deep

Further work is needed before deciding which therapeutic strategy-targeting CD29, CD61 or TGFb-has the best chance in scleroderma.

"A large body of evidence points to a role of TGFb in scleroderma, and Dietz's team's work further supports this," said Thomas Hultsch, senior medical director of translational medicine at Sanofi's Genzyme Corp. unit. "Unraveling the mechanisms that control TGFb activation in the microenvironment of the dermis will be central for further development" of the team's findings.

Added Nabel, "Our reading is that Dietz suggests the integrin pathways may allow modulation of TGFb in a more controlled way, spatially and temporally, than targeting the cytokine directly. However, this claim remains preliminary at the present time."

Evnin agreed and said that targeting integrins b1 or b3 would probably be a better strategy than inhibiting TGFb "because the cytokine is involved in many biological processes and thus is not a good target for a chronic disease like scleroderma."

He added, "An obvious next step would be to compare the relative efficacy and safety of the integrin b3-blocking and integrin b1-activating approaches in the Fbn1-mutant mouse models."

Hultsch said that it also would be interesting to dissect the role of the specific TGFb isoforms TGFb1 (TGFB1), TGFb2 (TGFB2) and TGFb3 (TGFB3) in skin fibrosis using isoform-specific antibodies, inhibitors or knockout models.

Evnin said that one drawback of the Fbn1-mutant models is that they do not exhibit the potentially life-threatening internal organ fibrosis seen in patients with systemic scleroderma. "That does leave open to question whether targeting integrins or TGFb would also prevent or reverse that fibrosis. While this question can't be answered in mice, our hope is that the therapeutic effect would indeed be the same," he said.

According to Evnin, The Johns Hopkins University has filed a patent application covering the findings reported in Nature.

Dietz did not respond to queries about his team's follow-on studies in the Fbn1 models.

This week, Biogen Idec Inc. and the BioFocus subsidiary of Galapagos N.V. announced a three-year collaboration to identify and validate new targets in scleroderma. Under the terms of the deal, BioFocus will use its technology platform and human skin models to deliver new assays and previously unknown, validated targets to Biogen Idec. Galapagos said that the deal could net BioFocus up to $31 million. Other terms were not disclosed.

Haas, M.J. SciBX 6(44); doi:10.1038/scibx.2013.1248
Published online Nov. 14, 2013


1.   Gerber, E.E. et al. Nature; published online Oct. 9, 2013; doi:10.1038/nature12614
Harry C. Dietz, The Johns Hopkins University School of Medicine, Baltimore, Md.

2.   Dietz, H.C. et al. Nature 352, 337-339 (1991)

3.   Habashi, J.P. et al. Science 312, 117-121 (2006)

4.   Loeys, B.L. et al. Sci. Transl. Med. 2, 23ra20 (2010)

5.   Varga, J. & Pasche, B. Nat. Rev. Rheumatol. 5, 200-206 (2009)


Biogen Idec Inc. (NASDAQ:BIIB), Weston, Mass.

The Johns Hopkins University, Baltimore, Md.

The Johns Hopkins University School of Medicine, Baltimore, Md.

Galapagos N.V. (Euronext:GLPG; Pink:GLPYY), Mechelen, Belgium

Genzyme Corp., Cambridge, Mass.

Howard Hughes Medical Institute, Chevy Chase, Md.

McGill University, Montreal, Quebec, Canada

MPM Capital, South San Francisco, Calif.

Sanofi (Euronext:SAN; NYSE:SNY), Paris, France

Scleroderma Research Foundation, San Francisco, Calif.