The Novel p38 Inhibitor, Pamapimod, Inhibits Osteoclastogenesis and Counteracts Estrogen-Dependent Bone Loss in Mice.

ADAM12 Protein / metabolism Animals Enzyme Inhibitors / pharmacology Estrogens / metabolism Female Mice NFATC Transcription Factors / metabolism Osteoclasts / metabolism Osteoporosis / drug therapy Ovariectomy Pyridones / pharmacology Pyrimidines / pharmacology p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
ADAM12 OSTEOCLAST OSTEOPOROSIS p38

Journal

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
ISSN: 1523-4681
Titre abrégé: J Bone Miner Res
Pays: United States
ID NLM: 8610640

Informations de publication

Date de publication:
05 2019
Historique:
received: 12 05 2018
revised: 21 11 2018
accepted: 04 12 2018
pubmed: 8 1 2019
medline: 6 8 2020
entrez: 8 1 2019
Statut: ppublish

Résumé

Pamapimod (PAM) is a novel selective p38 mitogen-activated protein (MAP) kinase inhibitor proved to be effective in rheumatoid arthritis in phase 2 clinical trial. However, its effect on osteoclast-associated osteoporosis and the underlying mechanisms remain unclear. In this study, we showed that PAM suppressed receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation via inhibition of p38 phosphorylation and subsequent c-Fos and nuclear factor of activated T cells c1 (NFATc1) expression. In addition, the downregulated NFATc1 leads to reduced expression of its targeting gene disintegrin and metalloproteinase domain-containing protein 12 (ADAM12), which was further proven to be critical for osteoclastic bone resorption. Therefore, we treated ovariectomized (OVX) mice with PAM and revealed a protective effect of PAM on osteoporosis in vivo. In conclusion, our results demonstrated PAM can prevent OVX-induced bone loss through suppression of p38/NFATc1-induced osteoclast formation and NFATc1/ADAM12-associated bone resorption. © 2018 American Society for Bone and Mineral Research.

Identifiants

DOI: 10.1002/jbmr.3655 PMID: 30615802
pubmed: 30615802
doi: 10.1002/jbmr.3655
doi:

Substances chimiques

Enzyme Inhibitors 0
Estrogens 0
NFATC Transcription Factors 0
Nfatc1 protein, mouse 0
Pyridones 0
Pyrimidines 0
pamapimod 8S2C9V11K4
p38 Mitogen-Activated Protein Kinases EC 2.7.11.24
ADAM12 Protein EC 3.4.24.-
Adam12 protein, mouse EC 3.4.24.-

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

911-922

Commentaires et corrections

Type : ErratumIn

Informations de copyright

© 2018 American Society for Bone and Mineral Research.

Auteurs

Xiangde Zhao (X)

Department of Orthopaedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China.

Lei Ning (L)

Department of Orthopaedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China.

Ziang Xie (Z)

Department of Orthopaedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China.

Zhiwei Jie (Z)

Department of Orthopaedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China.

Xiang Li (X)

Department of Orthopaedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China.

Xinyu Wan (X)

First Clinical Medical College, Wenzhou Medical University, Wenzhou, China.

Xuewu Sun (X)

Department of Orthopaedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China.

Bao Huang (B)

Department of Orthopaedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China.

Pan Tang (P)

Department of Orthopedics, Huzhou Central Hospital, Zhejiang University Huzhou Hospital, Huzhou, China.

Shuying Shen (S)

Department of Orthopaedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China.

An Qin (A)

Department of Orthopaedics, Shanghai Key Laboratory of Orthopaedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

Yan Ma (Y)

Department of Orthopaedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Lu Song (L)

Department of Oral Medicine, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Shunwu Fan (S)

Department of Orthopaedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China.

Shuanglin Wan (S)

Department of Orthopaedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Glycoprotéines › Protéines ADAM › Protéine ADAM12 › The Novel p38 Inhibitor, Pamapimod, Inhibits...
questionsmedicales.fr › Eucaryotes › Animaux › The Novel p38 Inhibitor, Pamapimod, Inhibits...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › The Novel p38 Inhibitor, Pamapimod, Inhibits...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Effets physiologiques des médicaments › Hormones, substituts d'hormones et antagonistes d'hormones › Hormones › Oestrogènes › The Novel p38 Inhibitor, Pamapimod, Inhibits...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › The Novel p38 Inhibitor, Pamapimod, Inhibits...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription NFATC › The Novel p38 Inhibitor, Pamapimod, Inhibits...
questionsmedicales.fr › Cellules › Cellules myéloïdes › Ostéoclastes › The Novel p38 Inhibitor, Pamapimod, Inhibits...
questionsmedicales.fr › Maladies métaboliques et nutritionnelles › Maladies métaboliques › Maladies osseuses métaboliques › Ostéoporose › The Novel p38 Inhibitor, Pamapimod, Inhibits...
questionsmedicales.fr › Procédures de chirurgie opératoire › Procédures de chirurgie urogénitale › Procédures de chirurgie gynécologique › Ovariectomie › The Novel p38 Inhibitor, Pamapimod, Inhibits...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pyridines › Pyridones › The Novel p38 Inhibitor, Pamapimod, Inhibits...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pyrimidines › The Novel p38 Inhibitor, Pamapimod, Inhibits...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Mitogen-Activated Protein Kinases › p38 Mitogen-Activated Protein Kinases › The Novel p38 Inhibitor, Pamapimod, Inhibits...