Center for Molecular Medicine Cologne

Thomas Krieg - SRG 02

The role of activated fibroblasts in fibrosis – scleroderma as a model disease

Introduction

Alteration of connective tissue is a hallmark of many common diseases. A tightly controlled balance of synthesis and degradation is crucial for guaranteeing the physiological function of bone, cartilage, tendon and skin and all other organs in which connective tissue represents the scaffold.

Our group concentrates on skin diseases with the aim to unravel the cellular and molecular basis of fibrotic and degenerative processes. These are common burdens leading to chronic ulcerations, inadequate healing, reduced strength or fibrotic responses. The resulting diseases represent a major medical and socio-economic problem, and care for these patients needs to be improved.

Our Aims

The Krieg lab aims to better understand mechanisms controlling activation of fibroblasts with a special focus on activation by fibroblast communication with the surrounding extracellular matrix (ECM).

We want to translate our findings into understanding the molecular basis of diseases associated with excessive fibroblast activation and to design targeted therapies.

Our group aims at investigating the mechanisms underlying the control of connective tissue synthesis and the role of cell-matrix interactions.

Fibroblasts represent a heterogeneous group of cells, which derive from different cellular origins, and are the key cells orchestrating the formation of connective tissues following any type of injury. Their phenotype and function are regulated by interactions with the surrounding extracellular matrix (ECM), mediated by specific receptors, and by the activity of growth factors and cytokines through complex paracrine and autocrine regulatory loops.

As a model we use fibroblasts obtained from patients with scleroderma, an autoimmune-driven chronic fibrotic disease that involves the skin but can also affect many other organs. To ensure that results from our experimental work gain direct entry into translational applications, we have initiated a large clinical network for scleroderma patients together with the Department of Dermatology.

Selected publications

Wiestner M, Krieg T, Hörlein D, Glanville RW, Fietzek PP, Müller PK. (1979). Inhibiting effect of procollagen peptides on collagen biosynthesis in fibroblast cultures. J Biol Chem 254, 7016-7023.

Weber L, Kirsch E, Müller PK, Krieg T. (1984). Collagen type distribution and macromolecular organization of connective tissue in different layers of human skin. J Invest Dermatol 82, 156-160.

Krieg T, Langer I, Gerstmeier H, Keller J, Mensing H, Goerz G, Timpl R. (1986). Type III collagen aminopropeptide levels in serum of patients with progressive systemic scleroderma. J Invest Dermatol 87, 788-791.

LeRoy EC, Krieg T, Black C, Medsger TA Jr, Fleischmajer R, Rowell N, Jablonska S, Wollheim F. (1988). Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol 15, 202-205.

Langholz O, Rockel D, Mauch C, Koslowska E, Bank I, Krieg T, Eckes B. (1995). Collagen and collagenase gene expression in three-dimensional collagen lattices are differentially regulated by a1b1 and a2b1 integrins. J Cell Biol 131, 1903-1915.

Gabrielli Avvedimento EV, Krieg T. (2009). Scleroderma. New Engl J Med 360, 1989-2003.

Blumbach K, Zweers MC, Brunner G, Peters AS, Schmitz M, Schulz JN, Schild A, Denton CP, Sakai T, Faessler R, Krieg T, Eckes B. (2010). Defective granulation tissue formation in mice with specific ablation of integrin-linked kinase in fibroblasts - role of TGFb1 levels and RhoA activity. J Cell Sci 123, 3872-3883.

Radovanac K, Morgner J, Schulz JN, Blumbach K, Patterson C, Geiger T, Mann M, Krieg T, Eckes B, Faessler R, Wickström SA. (2013). Stabilization of integrin-linked kinase by the Hsp90-CHIP axis impacts cellular force generation, migration and the fibrotic response. EMBO J 32, 1409-1424.

Schulz JN, Nüchel J, Niehoff A, Bloch W, Schönborn K, Hayashi S, Kamper M, Brinckmann J, Plomann M, Paulsson M, Krieg T, Zaucke F, Eckes B. (2016). COMP-assisted collagen secretion - a novel intracellular function required for fibrosis. J Cell Sci 129, 706-716.

Nüchel J, Ghatak S, Zuk AV, Illerhaus A, Mörgelin M, Schönborn K, Blumbach K, Wickström SA, Krieg T, Sengle G, Plomann M, Eckes B. (2018). TGFB1 is secreted through an unconventional pathway dependent on the autophagic machinery and cytoskeletal regulators. Autophagy 14, 465-486.

Schönborn K, Willenborg S, Schulz JN, Imhof T, Eming SA, Quondamatteo F, Brinckmann J, Niehoff A, Paulsson M, Koch M, Eckes B, Krieg T. (2020). Role of collagen XII in skin homeostasis and repair. Matrix Biol 2020, Sep 2: S0945-053X(20)30087-1. doi: 10.1016/j.matbio. 2020 .08. 002.

Prof. Dr. Dr. h.c. Thomas Krieg CMMC Cologne
Prof. Dr. Dr. h.c. Thomas Krieg

Translational Matrix Biology

Principal Investigator SRG 02

Executive Board Member

Publications - Thomas Krieg

Link to PubMed

Group Members

Dr. Beate Eckes
Susanne Neumann         
Dr. Mugdha Sawant        
Dr. Katrin Schönborn         
Isabel Zeinert