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

• Published in: Stem cell reports Vol. 17; no. 3; pp. 616 - 632
• Main Authors: Franco, Rose Ann G., McKenna, Eamonn, Robey, Pamela G., Shajib, Md. Shaffiulah, Crawford, Ross W., Doran, Michael R., Futrega, Kathryn
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08-03-2022; Elsevier
• Subjects: adipogenesis; BMP inhibition; BMSC; Bone Marrow Cells - metabolism; Bone Morphogenetic Proteins - metabolism; Cell Differentiation - physiology; Chondrogenesis; differentiation; Humans; hypertrophy; Hypertrophy - metabolism; LDN 193189; mesenchymal stem cell; Mesenchymal Stem Cells; Osteogenesis; Pyrazoles; Pyrimidines; mesenchymal stem cell; adipogenesis; differentiation; BMSC; BMP inhibition; hypertrophy; LDN 193189; chondrogenesis; osteogenesis
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2022.01.016

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.
•LDN 193189 does not modify BMSC chondrogenic or hypertrophic differentiation•LDN 193189 obstructs exogenous BMP-2 signaling, preventing osteogenesis and adipogenesis•LDN 193189 does not modify BMSC behavior in adipogenic induction medium
Efficacious use of BMSCs in cartilage repair requires mitigation of these cells' propensity to undergo hypertrophic differentiation. In this article, Futrega et al. evaluated whether obstructing BMP signaling with the small molecule LDN 193189 prevented hypertrophy in chondrogenically induced BMSC. They showed that LDN 193189 does obstruct BMP-2 signaling but that this was insufficient to prevent BMSC hypertrophy.