12-Deoxyphorbol 13-acetate inhibits RANKL-induced osteoclastogenesis via the attenuation of MAPK signaling and NFATc1 activation

Delong Chen; Feifan Chu; Gangyu Zhang; Qingqing Wang; Ying Li; Meng Zhang; Qi He; Junzheng Yang; Haibin Wang; Ping Sun; Jiake Xu; Peng Chen

doi:10.1016/j.intimp.2021.108177

12-Deoxyphorbol 13-acetate inhibits RANKL-induced osteoclastogenesis via the attenuation of MAPK signaling and NFATc1 activation

Int Immunopharmacol. 2021 Dec;101(Pt A):108177. doi: 10.1016/j.intimp.2021.108177. Epub 2021 Oct 7.

Authors

Delong Chen¹, Feifan Chu², Gangyu Zhang³, Qingqing Wang⁴, Ying Li⁵, Meng Zhang⁶, Qi He³, Junzheng Yang³, Haibin Wang⁷, Ping Sun⁸, Jiake Xu⁹, Peng Chen¹⁰

Affiliations

¹ Department of Orthopaedic Surgery, Clifford Hospital, Jinan University, Guangzhou 510006, China.
² The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, China.
³ Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
⁴ Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China.
⁵ Department of Orthopaedic Surgery, The Third Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510360, China.
⁶ Department of Orthopedics, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou 450003, China.
⁷ Department of Orthopaedic Surgery, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
⁸ Department of Endocrinology, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou 510000, China.
⁹ School of Biomedical Sciences, University of Western Australia, Perth, Western Australia 6009, Australia.
¹⁰ Department of Orthopaedic Surgery, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510405, China. Electronic address: docchen777@gmail.com.

PMID: 34626872
DOI: 10.1016/j.intimp.2021.108177

Abstract

Osteoporosis, characterized by bone loss and microstructure damage, occurs when osteoclast activity outstrips osteoblast activity. Natural compounds with inhibitory effect on osteoclast differentiation and function have been evidenced to protect from osteoporosis. After multiple compounds screening, 12-deoxyphorbol 13-acetate (DPA) was found to decline RANKL-induced osteoclastogenesis dose-dependently by attenuating activities of NFATc1 and c-Fos, followed by decreasing the level of osteoclast function-associated genes and proteins including Acp5, V-ATPase-d2 and CTSK. Mechanistically, we found that DPA suppressing RANKL-induced downstream signaling pathways, including MAPK signaling pathway and calcium oscillations. Furthermore, the in vivo efficacy of DPA was further confirmed in an OVX-induced osteoporosis mice model. Collectively, the results in our presentation reveal that DPA might be a promising compound to manage osteoporosis.

Keywords: 12-Deoxyphorbol 13-acetate; MAPK; NFATc1; Osteoclast; Osteoporosis.

MeSH terms

Animals
Disease Models, Animal
Drug Evaluation, Preclinical
Female
Humans
MAP Kinase Signaling System / drug effects
MAP Kinase Signaling System / immunology
Mice
NFATC Transcription Factors / antagonists & inhibitors*
NFATC Transcription Factors / metabolism
Osteoclasts / drug effects
Osteoclasts / physiology
Osteogenesis / drug effects
Osteogenesis / immunology
Osteoporosis / drug therapy*
Osteoporosis / immunology
Phorbol Esters / pharmacology*
Phorbol Esters / therapeutic use
RAW 264.7 Cells

Substances

NFATC Transcription Factors
Nfatc1 protein, mouse
Phorbol Esters
prostratin