Inhibition of BMP signaling with LDN 193189 can influence bone marrow stromal cell fate but does not prevent hypertrophy during chondrogenesis

Rose Ann G Franco; Eamonn McKenna; Pamela G Robey; Md Shaffiulah Shajib; Ross W Crawford; Michael R Doran; Kathryn Futrega

doi:10.1016/j.stemcr.2022.01.016

Inhibition of BMP signaling with LDN 193189 can influence bone marrow stromal cell fate but does not prevent hypertrophy during chondrogenesis

Stem Cell Reports. 2022 Mar 8;17(3):616-632. doi: 10.1016/j.stemcr.2022.01.016. Epub 2022 Feb 17.

Authors

Rose Ann G Franco¹, Eamonn McKenna¹, Pamela G Robey², Md Shaffiulah Shajib³, Ross W Crawford⁴, Michael R Doran⁵, Kathryn Futrega⁶

Affiliations

¹ Centre for Biomedical Technologies, School of Mechanical, Medical and Process Engineering, Faculty of Engineering, Queensland University of Technology (QUT), Brisbane, Australia; Translational Research Institute, Brisbane, Australia.
² Skeletal Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
³ Centre for Biomedical Technologies, School of Mechanical, Medical and Process Engineering, Faculty of Engineering, Queensland University of Technology (QUT), Brisbane, Australia; Translational Research Institute, Brisbane, Australia; School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia.
⁴ Centre for Biomedical Technologies, School of Mechanical, Medical and Process Engineering, Faculty of Engineering, Queensland University of Technology (QUT), Brisbane, Australia.
⁵ Centre for Biomedical Technologies, School of Mechanical, Medical and Process Engineering, Faculty of Engineering, Queensland University of Technology (QUT), Brisbane, Australia; Translational Research Institute, Brisbane, Australia; Skeletal Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA; School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia; Mater Research Institute - University of Queensland, Brisbane, Australia. Electronic address: michael.doran@qut.edu.au.
⁶ Centre for Biomedical Technologies, School of Mechanical, Medical and Process Engineering, Faculty of Engineering, Queensland University of Technology (QUT), Brisbane, Australia; Translational Research Institute, Brisbane, Australia; Skeletal Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA. Electronic address: futregak2@nih.gov.

Abstract

Bone morphogenetic protein (BMP) cascades are upregulated during bone marrow-derived stromal cell (BMSC) chondrogenesis, contributing to hypertrophy and preventing effective BMSC-mediated cartilage repair. Previous work demonstrated that a proprietary BMP inhibitor prevented BMSC hypertrophy, yielding stable cartilage tissue. Because of the significant therapeutic potential of a molecule capable of hypertrophy blockade, we evaluated the capacity of a commercially available BMP type I receptor inhibitor with similar properties, LDN 193189, to prevent BMSC hypertrophy. Using 14-day microtissue chondrogenic induction cultures we found that LDN 193189 permitted BMSC chondrogenesis but did not prevent hypertrophy. LDN 193189 was sufficiently potent to counter mineralization and adipogenesis in response to exogenous BMP-2 in osteogenic induction cultures. LDN 193189 did not modify BMSC behavior in adipogenic induction cultures. Although LDN 193189 is effective in countering BMP signaling in a manner that influences BMSC fate, this blockade is insufficient to prevent hypertrophy.

Keywords: BMP inhibition; BMSC; LDN 193189; adipogenesis; chondrogenesis; differentiation; hypertrophy; mesenchymal stem cell; osteogenesis.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Intramural

MeSH terms

Bone Marrow Cells / metabolism
Bone Morphogenetic Proteins / metabolism
Cell Differentiation / physiology
Chondrogenesis*
Humans
Hypertrophy / metabolism
Mesenchymal Stem Cells*
Osteogenesis
Pyrazoles
Pyrimidines

Substances

Bone Morphogenetic Proteins
LDN 193189
Pyrazoles
Pyrimidines

Grants and funding

ZIA DE000380/ImNIH/Intramural NIH HHS/United States