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Higenamine Promotes Osteogenesis Via IQGAP1/SMAD4 Signaling Pathway and Prevents Age- and Estrogen-Dependent Bone
Hui Dong1, Ronghan Liu1,2, Ke Zou1
1Jinan Central Hospital, Shandong University, Jinan, China.
Abstract:
Osteoporosis is a common bone disease caused by an imbalance of bone resorption and formation that results in a loss of total bone density. SMAD2/3 signal transduction is known to play a crucial role in osteogenic differentiation through transforming growth factor-beta (TGF-β). By screening a library of small-molecule compounds, the current study identifies higenamine (HG) as an active osteogenic agent that could be a therapeutic candidate for osteoporosis. In vitro data demonstrated that HG effectively induced expressions of osteogenic markers in mouse bone marrow stromal cell (BMSCs) and preosteoblastic cell cultures. Further, HG treatment resulted in enhanced bone formation and prevented accelerated bone loss on two animal models that mimic spontaneous senile osteoporosis and postmenopausal osteoporosis. IQ motif-containing GTPase-activating protein 1 (IQGAP1) was confirmed as a novel target of HG, where HG appears to bind to the Glu-1019 site of IQGAP1 to exert its osteogenic effects. Data subsequently suggested that HG promoted phosphorylation of SMAD2/3 and regulated the SMAD2/3 pathway by inhibiting SMAD4 ubiquitination. Overall, the findings highlight HG as a new small-molecule drug to promote bone formation through SMAD2/3 pathway in osteoporosis. © 2023 American Society for Bone and Mineral Research (ASBMR).
Insights
Higenamine (HG) is a novel small-molecule drug that promotes bone formation. This compound treats osteoporosis by enhancing osteogenic markers and preventing bone loss via the SMAD2/3 pathway.
Area of Science:
- Molecular Biology
- Cell Biology
- Pharmacology
Background:
- Osteoporosis is a bone disease characterized by decreased bone density due to an imbalance between bone resorption and formation.
- Transforming growth factor-beta (TGF-β) signaling, particularly SMAD2/3 transduction, is critical for osteogenic differentiation.
Purpose of the Study:
- To identify novel small-molecule compounds that can promote bone formation and serve as potential therapeutics for osteoporosis.
- To investigate the mechanism of action of higenamine (HG) in promoting osteogenesis and its therapeutic potential for osteoporosis.
Main Methods:
- Screening of small-molecule compounds to identify osteogenic agents.
- In vitro studies using mouse bone marrow stromal cells (BMSCs) and preosteoblastic cells to assess HG's effect on osteogenic markers.
- In vivo studies using animal models of senile and postmenopausal osteoporosis to evaluate HG's impact on bone formation and bone loss.
- Identification of IQ motif-containing GTPase-activating protein 1 (IQGAP1) as a target of HG and investigation of its interaction site.
- Analysis of HG's effect on SMAD2/3 phosphorylation and SMAD4 ubiquitination to elucidate its mechanism of action.
Main Results:
- Higenamine (HG) was identified as an active osteogenic agent.
- HG treatment upregulated osteogenic markers in vitro and enhanced bone formation while preventing bone loss in vivo.
- IQ motif-containing GTPase-activating protein 1 (IQGAP1) was identified as a direct target of HG, binding at the Glu-1019 site.
- HG promoted SMAD2/3 phosphorylation and regulated the SMAD2/3 pathway by inhibiting SMAD4 ubiquitination.
Conclusions:
- Higenamine (HG) is a promising small-molecule therapeutic candidate for osteoporosis.
- HG promotes bone formation by targeting IQGAP1 and modulating the SMAD2/3 signaling pathway.
- The findings provide a novel therapeutic strategy for osteoporosis through small-molecule intervention targeting the SMAD2/3 pathway.
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