Matrine derivate MASM uncovers a novel function for ribosomal protein S5 in osteoclastogenesis and postmenopausal osteoporosis.

Abstract

Postmenopausal osteoporosis (POMP) is a public health problem characterized by decreased bone density and increased fracture risk. Over-activated osteoclastogenesis plays a vital role in POMP. Here we developed a novel bioactive compound MASM (M19) based on sophocarpine. Although it showed no significant effects on osteogenesis and adipogenesis for bone marrow-derived mesenchymal stem cells (BMSCs) in vitro, it could significantly inhibit RANKL/M-CSF induced osteoclastogenesis through suppressing NF-κB, MAPKs and PI3K/Akt pathways in vitro and ameliorate bone loss in ovariectomized mice in vivo. Ribosomal protein s5 (RPS5) has been identified as a target of M19 and regulates PI3K/Akt, NF-κB and MAPKs pathways in osteoclastogenesis. Overexpressions of RPS5 synergistically inhibited osteoclastogenesis with M19 while silencing RPS5 compromised M19 inhibitory effects on osteoclastogenesis in vitro. Among the three pathways, Akt plays a major role in M19 effects. The Akt activator SC79 partially reversed the inhibitory effects on osteoclastogenesis by M19 and RPS5-knocking-down. It indicates that RPS5 serves as a potential candidate target for inhibiting osteoclastogenesis and osteoporosis therapy and M19 is a promising agent for POMP treatment.

• Authors: Xiao Chen, Xin Zhi, Liehu Cao, Weizong Weng, Panpan Pan, Honggang Hu, Chao Liu, Qingjie Zhao, Qirong Zhou, Jin Cui, Jiacan Su
• Journal: Cell death & disease (Cell Death Dis) Vol. 8 Issue 9 Pg. e3037 (09 07 2017) ISSN: 2041-4889 [Electronic] England
• PMID: 28880271 (Publication Type: Journal Article, Retracted Publication)

Chemical References

• 2-amino-6-chloro-alpha-cyano-3-(ethoxycarbonyl)-4H-1-benzopyran-4-acetic acid ethyl ester
• Acetates
• Alkaloids
• Benzopyrans
• Bone Density Conservation Agents
• NF-kappa B
• Phosphoinositide-3 Kinase Inhibitors
• RANK Ligand
• Ribosomal Proteins
• Tnfsf11 protein, mouse
• ribosomal protein S5
• sophocarpine
• Macrophage Colony-Stimulating Factor
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinases

Topics

• Acetates (pharmacology)
• Alkaloids (chemical synthesis, pharmacology)
• Animals
• Benzopyrans (pharmacology)
• Bone Density (drug effects)
• Bone Density Conservation Agents (chemical synthesis, pharmacology)
• Bone Marrow Cells (cytology, drug effects, metabolism)
• Disease Models, Animal
• Female
• Gene Expression Regulation
• Humans
• Macrophage Colony-Stimulating Factor (antagonists & inhibitors, pharmacology)
• Mesenchymal Stem Cells (cytology, drug effects, metabolism)
• Mice
• Mitogen-Activated Protein Kinases (antagonists & inhibitors, genetics, metabolism)
• NF-kappa B (antagonists & inhibitors, genetics, metabolism)
• Osteoclasts (drug effects, metabolism, pathology)
• Osteogenesis (drug effects, genetics)
• Osteoporosis, Postmenopausal (drug therapy, etiology, genetics, pathology)
• Ovariectomy (adverse effects)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Primary Cell Culture
• Proto-Oncogene Proteins c-akt (agonists, antagonists & inhibitors, genetics, metabolism)
• RANK Ligand (antagonists & inhibitors, pharmacology)
• Ribosomal Proteins (agonists, genetics, metabolism)
• Signal Transduction