title: Protocatechuic Acid Attenuates Osteoclastogenesis by Downregulating JNK/c-Fos/NFATc1 Signaling and Prevents Inflammatory Bone Loss in Mice.
abstract: Protocatechuic acid (PCA) plays a critical role in nutritional metabolism; it is a major metabolite of anthocyanins, which are flavonoids with a range of health benefits. PCA has a variety of biological activities including anti-oxidant, antiinflammatory, anti-apoptosis, and anti-microbial activities. However, the pharmacological effect of PCA, especially on osteoclastogenesis, remains unknown. We examined the effect of PCA on receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation and bone resorption. PCA dose-dependently inhibited RANKL-induced osteoclast differentiation in mouse bone marrow macrophages (BMMs) and suppressed the bone-resorbing activity of mature osteoclasts. At the molecular level, PCA suppressed RANKL-induced phosphorylation of JNK among MAPKs only, without significantly affecting the early signaling pathway. PCA also suppressed RANKL-stimulated expression of c-Fos and nuclear factor of activated T cells c1 (NFATc1) at the mRNA and protein levels, without altering c-Fos mRNA expression. Additionally, PCA down-regulated the expression of downstream osteoclastogenesis-related genes including β3-integrin, DC-STAMP, OC-STAMP, Atp6v0d2, CTR, and CtsK. Mice treated with PCA efficiently recovered from lipopolysaccharide-induced bone loss in vivo. Thus, PCA inhibits RANKL-induced osteoclast differentiation and function by suppressing JNK signaling, c-Fos stability, and expression of osteoclastic marker genes. These results suggest that PCA could be useful in treatment of inflammatory bone disorders.
authors.affiliation: Department of Anatomy, School of Medicine, Wonkwang University, Iksan, Jeonbuk, 570-749, Republic of Korea.
authors.forename: Sun-Hyang
authors.initials: SH
authors.lastname: Park
authors.affiliation: Imaging Science-based Lung and Bone Diseases Research Center, Wonkwang University, Iksan, Jeonbuk, 570-749, Republic of Korea.
authors.forename: Ju-Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Center for Metabolic Function Regulation, Wonkwang University, Iksan, Jeonbuk, 570-749, Republic of Korea.
authors.forename: Yoon-Hee
authors.initials: YH
authors.lastname: Cheon
authors.affiliation: Department of Anatomy, School of Medicine, Wonkwang University, Iksan, Jeonbuk, 570-749, Republic of Korea.
authors.forename: Jong Min
authors.initials: JM
authors.lastname: Baek
authors.affiliation: Department of Anatomy, School of Medicine, Wonkwang University, Iksan, Jeonbuk, 570-749, Republic of Korea.
authors.forename: Sung-Jun
authors.initials: SJ
authors.lastname: Ahn
authors.affiliation: Imaging Science-based Lung and Bone Diseases Research Center, Wonkwang University, Iksan, Jeonbuk, 570-749, Republic of Korea.|Department of Radiology, School of Medicine, Wonkwang University, Iksan, Jeonbuk, 570-749, Republic of Korea.
authors.forename: Kwon-Ha
authors.initials: KH
authors.lastname: Yoon
authors.affiliation: Imaging Science-based Lung and Bone Diseases Research Center, Wonkwang University, Iksan, Jeonbuk, 570-749, Republic of Korea.|Division of Rheumatology, Department of Internal Medicine, Wonkwang University, Iksan, Jeonbuk, 570-749, Republic of Korea.|Institute for Skeletal Disease, Wonkwang University, Iksan, Jeonbuk, 570-749, Republic of Korea.
authors.forename: Myeung Su
authors.initials: MS
authors.lastname: Lee
authors.affiliation: Department of Anatomy, School of Medicine, Wonkwang University, Iksan, Jeonbuk, 570-749, Republic of Korea.|Imaging Science-based Lung and Bone Diseases Research Center, Wonkwang University, Iksan, Jeonbuk, 570-749, Republic of Korea.|Institute for Skeletal Disease, Wonkwang University, Iksan, Jeonbuk, 570-749, Republic of Korea.
authors.forename: Jaemin
authors.initials: J
authors.lastname: Oh
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects; D001862:Bone Resorption / Q000188:drug therapy* / Q000517:prevention & control; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D062385:Hydroxybenzoates / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D053245:RANK Ligand / Q000494:pharmacology
chemical_list: D062385:Hydroxybenzoates; D008070:Lipopolysaccharides; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; C009091:protocatechuic acid
keywords: JNK; LPS; NFATc1; RANKL; osteoclast; protocatechuic acid