Bone anti-resorptive effects of coumarins on RANKL downstream cellular signaling: a systematic review of the literature

Background: Members of the botanical families Apiaceae/Umbelliferae, Asteraceae, Fabaceae/Leguminosae, and Thymelaeaceae are rich in coumarins and have traditionally been used as ethnomedicines in many regions including Europe, Asia, and South America. Coumarins are a class of secondary metabolites that are widely present in plants, fungi, and bacteria and exhibit several pharmacological, biochemical, and therapeutic effects. Recently, many plants rich in coumarins and their derivatives were found to affect bone metabolism. Objective: To review scientific literature describing the mechanisms of action of coumarins in osteoclastogenesis and bone resorption. Materials and methods: For this systematic review, the PubMed, Scopus, and Periodical Capes databases and portals were searched. We included in vitro research articles published between 2010 and 2020 that evaluated coumarins using osteoclastogenic markers. Results: Coumarins have been reported to downregulate RANKL-RANK signaling and various downstream signaling pathways required for osteoclast development, such as NF-kappa B, MAPK, Akt, and Ca2+ signaling, as well as pathways downstream of the nuclear factor of activated T-cells (NFATc1), including tartrate-resistant acid phosphatase (TRAP), cathepsin K (CTSK), and matrix metalloproteinase 9 (MMP-9). Conclusions: Coumarins primarily inhibit osteoclast differentiation and activation by modulating different intracellular signaling pathways; therefore, they could serve as potential candidates for controlled randomized clinical trials aimed at improving human bone health.