Discoidin domain receptor 2 regulates aberrant mesenchymal lineage cell fate and matrix organization

Chase A. Pagani, Alec C. Bancroft, Robert J. Tower, Nicholas Livingston, Yuxiao Sun, Jonathan Y. Hong, Robert N. Kent, Amy L. Strong, Johanna H. Nunez, Jessica Marie R. Medrano, Nicole Patel, Benjamin A. Nanes, Kevin M. Dean, Zhao Li, Chunxi Ge, Brendon M. Baker, Aaron W. James, Stephen J. Weiss, Renny T. Franceschi, Benjamin Levi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Extracellular matrix (ECM) interactions regulate both the cell transcriptome and proteome, thereby determining cell fate. Traumatic heterotopic ossification (HO) is a disorder characterized by aberrant mesenchymal lineage (MLin) cell differentiation, forming bone within soft tissues of the musculoskeletal system following traumatic injury. Recent work has shown that HO is influenced by ECM-MLin cell receptor signaling, but how ECM binding affects cellular outcomes remains unclear. Using time course transcriptomic and proteomic analyses, we identified discoidin domain receptor 2 (DDR2), a cell surface receptor for fibrillar collagen, as a key MLin cell regulator in HO formation. Inhibition of DDR2 signaling, through either constitutive or conditional Ddr2 deletion or pharmaceutical inhibition, reduced HO formation in mice. Mechanistically, DDR2 perturbation alters focal adhesion orientation and subsequent matrix organization, modulating Focal Adhesion Kinase (FAK) and Yes1 Associated Transcriptional Regulator and WW Domain Containing Transcription Regulator 1 (YAP/TAZ)–mediated MLin cell signaling. Hence, ECM-DDR2 interactions are critical in driving HO and could serve as a previously unknown therapeutic target for treating this disease process.

Original languageEnglish
Article numbereabq6152
JournalScience Advances
Volume8
Issue number51
DOIs
StatePublished - Dec 2022
Externally publishedYes

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