Fibromodulin and chondroadherin in connective tissue homeostasis

Research output: ThesisDoctoral Thesis (compilation)

Abstract

Connective tissue contains a prominent extracellular matrix (ECM), which provides for physiological and
mechanical properties. Intra- and inter-molecular interactions between proteins in this ECM provide for the
formation of molecular networks. These interactions determine the shape of the tissue as well as cell behavior.
This thesis is focused on the leucine-rich repeat proteoglycans fibromodulin and chondroadherin and their
interactions with other proteins in the ECM.
The N-terminal domain of fibromodulin has a highly negative charge due to the presence of the posttranslational
modification of O-sulfate on tyrosine residues. We hypothesized that this domain could mimic heparin binding to
proteins containing domains with clusters of basic amino acids. Interactions to synthetic peptides with heparin
binding properties, representing the basic domains of the ECM proteins chondroadherin and PRELP and the
cytokine oncostatin M were identified. Additional interactions were found with the heparin binding proteins
MMP-13, basic FGF, type IX collagen, thrombospondin-1 and interleukine-10. Fibromodulin can then function as
a linker in the ECM, binding proteins containing basic domains through its N-terminal domain and other proteins,
e.g. collagen. This may determine the appearance and properties of the collagen network. Fibromodulin may also
function to sequester proteases and bioactive molecules in the matrix.
Further, other functions of this domain were found. Presence of the domain enhanced the overall affinity of fulllength
fibromodulin to collagen and it positively regulated collagen fibril formation in vitro. The regulatory role
was evaluated by electron microscopy that showed involvement of the domain in the fine-tuning of collagen
molecules assembly into highly organized fiber structures.
The C-terminal domain of chondroadherin contains a cluster of basic amino acids, which besides binding
fibromodulin, binds heparin. This thesis describes interaction of this domain with heparan sulfate chains attached
to a cell surface proteoglycan. Upon binding this short peptide stimulated bound chondrocytes to spread and
increased the attachment through integrins, which resulted in the formation of focal adhesions. Further, the short
peptide elicited cell signaling via the MAPK/ERK signaling pathway. Chondroadherin exists in two forms, where
one of the forms represents a cleavage product that lacks the last nine amino acids, i.e. including the heparin
binding site. This cleavage may play an important role in tissue homeostasis through feedback regulation to the
cell.
Finally, the integrin binding sequence of chondroadherin was identified by protease digestion of the protein
followed by mass spectrometry. The domain was shown to be located in one of the C-terminal disulfide loop
structures. Cells adhered to a peptide containing the integrin binding site remain rounded, but yet rapidly induced
MAPK/ERK signaling pathway. Thus, binding may be central for maintaining the chondrocyte phenotype and
homeostasis of adult cartilage, e.g. through release of growth factors, proteases and molecules for matrix
assembly.
This thesis describes biologically active domains of the protein fibromodulin and chondroadherin. Binding of the
described domains to other molecules is proposed to be important for the ECM assembly and how cells
communicate with the surrounding extracellular matrix.

Details

Authors
  • Viveka Tillgren
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Rheumatology and Autoimmunity

Keywords

  • Collagen, integrin, cell surface proteoglycan, extracellular matrix, and small leucine-rich repeat proteoglycan.
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
Award date2013 Nov 7
Publisher
  • Lund University, Faculty of Medicine, Department of Clinical Sciences, Section for Molecular Skeletal Biology and Rheumatology
Print ISBNs978-91-87449-90-1
Publication statusPublished - 2013
Publication categoryResearch

Bibliographic note

Defence details Date: 2013-11-07 Time: 09:00 Place: Rune Grubb-salen, BMC, Lund External reviewer(s) Name: Hardingham, Timothy Title: [unknown] Affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Science, University of Manchester, UK --- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Connective Tissue Biology (013230151)

Related research output

Lisbet Haglund, Viveka Tillgren, Patrik Önnerfjord & Dick Heinegård, 2013, In : Journal of Biological Chemistry. 288, 2, p. 995-1008

Research output: Contribution to journalArticle

Lisbet Haglund, Viveka Tillgren, Laura Addis, Christina Wenglén, Anneliese Recklies & Dick Heinegård, 2011, In : Journal of Biological Chemistry. 286, 5, p. 3925-3934

Research output: Contribution to journalArticle

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