Harmine targets inhibitor of DNA binding‐2 and activator protein‐1 to promote preosteoclast PDGF‐BB production

Abstract

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.

Formononetin attenuates osteoclast differentiation and calcium loss by mediating transcription factor AP‐1 in type I diabetic mice

“…Activating protein 1 (AP‐1) is a dimeric transcription factor that is comprised with cellular Jun (c‐Jun), cellular Fos (c‐Fos), or activating transcription factor subunit. [ 8 ] Emerging evidence reveals that activation of AP1 components is required for osteoclast differentiation [ 9–11 ] and can serve as antiosteoporotic targets. [ 9,11 ] Both glucocorticoid‐ and ovariectomy (OVX)‐induced osteoporosis, AP‐1 is activated and mediates osteoclast‐specific gene expression, such as acid phosphatase 5, tartrate‐resistant (Acp5), cathepsin K (Ctsk), and matrix metallopeptidase 9 (Mmp9).…”

Targeting type H vessels in bone‐related diseases

“…Ovariectomized (OVX) mice and rats generated by surgical excision of both ovaries are generally used as animal models for simulating postmenopausal osteoporosis to study aetiology and evaluate medical interventions. Harmine, a natural tricyclic β‐carboline alkaloid, can prevent bone loss in OVX mice by promoting type H vessel formation, primarily by increasing the secretion of platelet‐derived growth factor‐BB (PDGF‐BB) by preosteoclasts 28,29 . Gushukang, a traditional herbal compound used in Chinese medicine for the treatment of osteoporosis, could also induce type H vessel formation via elevated HIF‐1α expression in mice 30 .…”

“…Harmine, a natural tricyclic β‐carboline alkaloid, can prevent bone loss in OVX mice by promoting type H vessel formation, primarily by increasing the secretion of platelet‐derived growth factor‐BB (PDGF‐BB) by preosteoclasts. 28 , 29 Gushukang, a traditional herbal compound used in Chinese medicine for the treatment of osteoporosis, could also induce type H vessel formation via elevated HIF‐1α expression in mice. 30 It was also discovered that intraperitoneally administered deferoxamine (DFO, an HIF‐1α agonist) significantly increased the number of intraosseous type H vessels and surrounding osteoprogenitor cells, resulting in significantly improved BMD in the femur of OVX mice 9 , 31 (Figure 2 ).…”