An N-cyanoamide derivative of lithocholic acid co-operates with lysophosphatidic acid to promote human osteoblast (MG63) differentiation

Mansell, Jason P.; Tanatani, Aya; Kagechika, Hiroyuki

Abstract

Less-calcaemic vitamin D receptor (VDR) agonists have the potential to promote osteoblast maturation in a bone regenerative setting. The emergence of lithocholic acid (LCA) as a bona fide VDR agonist holds promise as an adjunct for arthroplasty following reports that it was less calcaemic than calcitriol (1,25D). However, LCA and some earlier derivatives, e.g., LCA acetate, had to be used at much higher concentrations than 1,25D to elicit comparable effects on osteoblasts. However, recent developments have led to the generation of far more potent LCA derivatives that even outperform the efficacy of 1,25D. These new compounds include the cyanoamide derivative, Dcha-150 (also known as AY2-79). In light of this significant development, we sought to ascertain the ability of Dcha-150 to promote human osteoblast maturation by monitoring alkaline phosphatase (ALP) and osteocalcin (OC) expression. The treatment of MG63 cells with Dcha-150 led to the production of OC. When Dcha-150 was co-administered with lysophosphatidic acid (LPA) or an LPA analogue, a synergistic increase in ALP activity occurred, with Dcha-150 showing greater potency compared to 1,25D. We also provide evidence that this synergy is likely attributed to the actions of myocardin-related transcription factor (MRTF)–serum response factor (SRF) gene transcription following LPA-receptor-induced cytoskeletal reorganisation.

• Journal Article Type: Article
• Acceptance Date: Jul 6, 2023
• Online Publication Date: Jul 13, 2023
• Publication Date: Jul 13, 2023
• Deposit Date: Aug 31, 2023
• Publicly Available Date: Sep 5, 2023
• Journal: Biomolecules
• Electronic ISSN: 2218-273X
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 13
• Issue: 7
• Article Number: 1113
• DOI: https://doi.org/10.3390/biom13071113
• Keywords: Molecular Biology, Biochemistry
• Public URL: https://uwe-repository.worktribe.com/output/10985789