Osteogenic mechanism of chlorogenic acid and its application in clinical practice

Abstract

Natural polyphenols may have a role in counteracting oxidative stress, which is associated with aging and several bone-related diseases. Chlorogenic acid (CGA) is a naturally occurring polyphenolic compound formed by the esterification of caffeic and quininic acids with osteogenic, antioxidant, and anti-inflammatory properties. This review discusses the potential of CGA to enhance osteogenesis by increasing the osteogenic capacity of mesenchymal stem cells (MSCs), osteoblast survival, proliferation, differentiation, and mineralization, as well as its ability to attenuate osteoclastogenesis by enhancing osteoclast apoptosis and impeding osteoclast regeneration. CGA can be involved in bone remodeling by acting directly on pro-osteoclasts/osteoblasts or indirectly on osteoclasts by activating the nuclear factor kB (RANK)/RANK ligand (RANKL)/acting osteoprotegerin (OPG) system. Finally, we provide perspectives for using CGA to treat bone diseases.

Keywords: chlorogenic acid; osteoblast; osteoclast; osteoporosis; periodontitis.

FIGURE 1

(A) 3D structure of chlorogenic acid; (B) Molecular formula of CGA.

FIGURE 2

Pharmacological effects of CGA CGA has a variety of different pharmacological effects, such as antioxidant activity (Khochapong et al., 2021), antiviral, anti-inflammatory, antibacterial (Munteanu and Apetrei, 2021), antithrombotic, and antitumor activities (Ye et al., 2020).

FIGURE 3

Chlorogenic acid metabolites (Zeng et al., 2022). The metabolic process of CGA and the structure and molecular formula of 37 metabolites.

FIGURE 4

In vivo metabolism of chlorogenic acid (A) CGA is scarcely metabolized but can interact with the oral microbiota; (B) In the stomach and small intestine, chlorogenic acid (CGA) is metabolized into caffeic acid and quinic acid; (C) Upon entering the liver, caffeic acid is metabolized into ferulic acid and isoferulic acid, while quinic acid is converted into gallic acid, which is further degraded into p-hydroxybenzoic acid and syringic acid; (D) After entering the cecum in the form of CA and QA, CA is hydrolyzed into p-coumaric acid, 3-HPA or HPPA, and QA is hydrolyzed into BA. Abbreviations: CA, caffeic acid; QA, quinic acid; FA, ferulic acid; isoFA, isoferulic acid; GA, gallic acid; pHBA, 4-Hydroxybenzoic acid; SA, Gallic acid; HPPA, hydroxyphenyl propionic acid; p-CA, p-Coumaric acid; 3-HPA, 3-hydroxyphenyl propionic acid; BA, Benzoic acid.

FIGURE 5

CGA promotes osteoblast proliferation and differentiation (A) The developmental process of osteoblasts; (B) CGA promote osteoblast proliferation in BMSC via the Shp2/PI3K/Akt/cyclin D1 pathway; (C) CGA could upregulate osteogenic gene expression and osteogenic protein synthesis by promoting cAMP expression.

FIGURE 6

OPG is upregulated after RANKL and RANK junction, thereby recruiting TRAF6 molecules and activating MAPK and NF-κB pathways, thereby promoting the expression of AP-1, BMP and c-FOS (early signals in endochondral bone formation). Chlorogenic acid inhibits osteoclast formation and differentiation by inhibiting TRAF6 and MAPK and NF-κB signalling pathways in osteoblasts. 7.

FIGURE 7

CGA forms a molecular docking with CysLT1R, which in turn reduces lipopolysaccharide-induced inflammation in gingival fibroblasts by affecting the CysLT1R/Nrf2/NLRP3 signalling pathway (Huang et al., 2022).