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.
MeSH terms
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Acetates / pharmacology
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Alkaloids / chemical synthesis
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Alkaloids / pharmacology*
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Animals
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Benzopyrans / pharmacology
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Bone Density / drug effects
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Bone Density Conservation Agents / chemical synthesis
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Bone Density Conservation Agents / pharmacology*
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Bone Marrow Cells / cytology
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Bone Marrow Cells / drug effects
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Bone Marrow Cells / metabolism
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Disease Models, Animal
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Female
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Gene Expression Regulation
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Humans
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Macrophage Colony-Stimulating Factor / antagonists & inhibitors
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Macrophage Colony-Stimulating Factor / pharmacology
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Mesenchymal Stem Cells / cytology
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Mesenchymal Stem Cells / drug effects
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Mesenchymal Stem Cells / metabolism
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Mice
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / metabolism
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Osteoclasts / drug effects*
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Osteoclasts / metabolism
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Osteoclasts / pathology
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Osteogenesis / drug effects*
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Osteogenesis / genetics
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Osteoporosis, Postmenopausal / drug therapy*
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Osteoporosis, Postmenopausal / etiology
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Osteoporosis, Postmenopausal / genetics
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Osteoporosis, Postmenopausal / pathology
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Ovariectomy / adverse effects
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Primary Cell Culture
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Proto-Oncogene Proteins c-akt / agonists
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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RANK Ligand / antagonists & inhibitors
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RANK Ligand / pharmacology
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Ribosomal Proteins / agonists
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Ribosomal Proteins / genetics*
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Ribosomal Proteins / metabolism
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Signal Transduction
Substances
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2-amino-6-chloro-alpha-cyano-3-(ethoxycarbonyl)-4H-1-benzopyran-4-acetic acid ethyl ester
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Acetates
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Alkaloids
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Benzopyrans
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Bone Density Conservation Agents
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NF-kappa B
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Phosphoinositide-3 Kinase Inhibitors
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RANK Ligand
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Ribosomal Proteins
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Tnfsf11 protein, mouse
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ribosomal protein S5
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sophocarpine
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Macrophage Colony-Stimulating Factor
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinases