Jie Huang 1 2, You-You Li 1 2, Kun Xia 1 2, Yi-Yi Wang 1 2, Chun-Yuan Chen 1 2, Meng-Lu Chen 1 2 3, Jia Cao 1 2, Zheng-Zhao Liu 1 2 3 4, Zhen-Xing Wang 1 2, Hao Yin 1 2, Xiong-Ke Hu 1 2, Zheng-Guang Wang 5, Yong Zhou 5, Hui Xie 1 2 3 4 6 7
J Cell Mol Med. 2021 May 7. doi: 10.1111/jcmm.16562.
Osteoporosis is one of the most common metabolic bone diseases affecting millions of people. We previously found that harmine prevents bone loss in ovariectomized mice via increasing preosteoclast platelet-derived growth factor-BB (PDGF-BB) production and type H vessel formation. However, the molecular mechanisms by which harmine promotes preosteoclast PDGF-BB generation are still unclear. In this study, we revealed that inhibitor of DNA binding-2 (Id2) and activator protein-1 (AP-1) were important factors implicated in harmine-enhanced preosteoclast PDGF-BB production. Exposure of RANKL-induced Primary bone marrow macrophages (BMMs), isolated from tibiae and femora of mice, to harmine increased the protein levels of Id2 and AP-1. Knockdown of Id2 by Id2-siRNA reduced the number of preosteoclasts as well as secretion of PDGF-BB in RANKL-stimulated BMMs administrated with harmine. Inhibition of c-Fos or c-Jun (components of AP-1) both reversed the stimulatory effect of harmine on preosteoclast PDGF-BB production. Dual-luciferase reporter assay analyses determined that PDGF-BB was the direct target of AP-1 which was up-regulated by harmine treatment. In conclusion, our data demonstrated a novel mechanism involving in the production of PDGF-BB increased by harmine, which may provide potential therapeutic targets for bone loss diseases.