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Inhibiting Heat Shock Protein 90 Attenuates Nucleus Pulposus Fibrosis and Pathologic Angiogenesis Induced by Macrophages via Down-Regulating Cell Migration-Inducing Protein.
Zhang, Shuo; Wang, Peng; Hu, Binwu; Lv, Xiao; Liu, Weijian; Chen, Songfeng; Shao, Zengwu.
Afiliação
  • Zhang S; Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • Wang P; Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • Hu B; Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • Lv X; Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • Liu W; Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • Chen S; Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. Electronic address: fccchensf@zzu.edu.cn.
  • Shao Z; Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: szwpro@163.com.
Am J Pathol ; 193(7): 960-976, 2023 07.
Article em En | MEDLINE | ID: mdl-37088454
ABSTRACT
Intervertebral disc (IVD) degeneration (IVDD) is usually accompanied by nucleus pulposus (NP) fibrosis and pathologic angiogenesis, which are possibly associated with macrophage infiltration. Previous research indicates a destructive role of macrophages and the protective effect of inhibiting heat shock protein 90 (HSP90) in IVDD. Herein, the effects of inhibiting HSP90 on NP fibrosis and pathologic angiogenesis induced by macrophages were investigated further. Single-cell RNA-sequencing analysis was used to classify fibrotic NP cell (NPC) clusters and healthy NPC clusters in human NP tissues. The fibrotic NPC clusters were possibly associated with angiogenesis-related biological processes. Immunostaining showed the spatial association between blood vessel ingrowth and macrophage infiltration, as well as elevated levels of cell migration-inducing protein (CEMIP) and vascular endothelial growth factor A in severely degenerated human IVD tissues. Particularly, HSP90 inhibitor tanespimycin (17-AAG) ameliorated macrophage-induced fibrotic phenotype of NPCs via inhibiting CEMIP. M2, but not M1, macrophages promoted the pro-angiogenic ability of endothelial cells, which was attenuated by 17-AAG or HSP90 siRNA. Reversing the fibrotic phenotype of NPCs by Cemip siRNA also mitigated the pro-angiogenic effects of M2-conditioned medium-treated NPCs. Moreover, the murine IVDD model supported the 17-AAG-induced amelioration of NP fibrosis and endothelial cell invasion in IVD tissues. In conclusion, inhibiting HSP90 attenuated two interrelated pathologic processes, NP fibrosis and pathologic angiogenesis, induced by macrophages via down-regulating CEMIP.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Degeneração do Disco Intervertebral / Núcleo Pulposo / Disco Intervertebral Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Degeneração do Disco Intervertebral / Núcleo Pulposo / Disco Intervertebral Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article