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Complete abrogation of key osteoclast markers with a membrane-anchored tissue inhibitor of metalloproteinase: a novel approach in the prevention of osteoclastogenesis
AIMS: Tissue inhibitors of metalloproteinases (TIMPs) are the endogenous inhibitors of the zinc-dependent matrix metalloproteinases (MMP) and A disintegrin and metalloproteinases (ADAM) involved in extracellular matrix modulation. The present study aims to develop the TIMPs as biologics for osteocla...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The British Editorial Society of Bone & Joint Surgery
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9680204/ https://www.ncbi.nlm.nih.gov/pubmed/36331083 http://dx.doi.org/10.1302/2046-3758.1111.BJR-2022-0147.R2 |
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author | Zhang, Yihe Jiang, Bingjie Zhang, Pengyuan Chiu, Sung K. Lee, Meng H. |
author_facet | Zhang, Yihe Jiang, Bingjie Zhang, Pengyuan Chiu, Sung K. Lee, Meng H. |
author_sort | Zhang, Yihe |
collection | PubMed |
description | AIMS: Tissue inhibitors of metalloproteinases (TIMPs) are the endogenous inhibitors of the zinc-dependent matrix metalloproteinases (MMP) and A disintegrin and metalloproteinases (ADAM) involved in extracellular matrix modulation. The present study aims to develop the TIMPs as biologics for osteoclast-related disorders. METHODS: We examine the inhibitory effect of a high affinity, glycosyl-phosphatidylinositol-anchored TIMP variant named ‘T1(PrαTACE)’ on receptor activator of nuclear factor kappa-Β ligand (RANKL)-induced osteoclast differentiation. RESULTS: Osteoclast progenitor cells transduced with T1(PrαTACE) failed to form tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts or exhibit bone-resorbing activity following treatment with RANKL. At the messenger RNA level, T1(PrαTACE) strongly attenuated expression of key osteoclast marker genes that included TRAP, cathepsin K, osteoclast stimulatory transmembrane protein (OC-STAMP), dendritic cell-specific transmembrane protein (DC-STAMP), osteoclast-associated receptor (OSCAR), and ATPase H(+)-transporting V0 subunit d2 (ATP6V0D2) by blocking autoamplification of nuclear factor of activated T cells 1 (NFATc1), the osteoclastogenic transcription factor. T1(PrαTACE) selectively extended p44/42 mitogen-activated protein kinase activation, an action that may have interrupted terminal differentiation of osteoclasts. Inhibition studies with broad-spectrum hydroxamate inhibitors confirmed that the anti-resorptive activity of T1(PrαTACE) was not reliant on its metalloproteinase-inhibitory activity. CONCLUSION: T1(PrαTACE) disrupts the RANKL-NFATc1 signalling pathway, which leads to osteoclast dysfunction. As a novel candidate in the prevention of osteoclastogenesis, the TIMP could potentially be developed for the treatment of osteoclast-related disorders such as osteoporosis. Cite this article: Bone Joint Res 2022;11(11):763–776. |
format | Online Article Text |
id | pubmed-9680204 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | The British Editorial Society of Bone & Joint Surgery |
record_format | MEDLINE/PubMed |
spelling | pubmed-96802042022-11-23 Complete abrogation of key osteoclast markers with a membrane-anchored tissue inhibitor of metalloproteinase: a novel approach in the prevention of osteoclastogenesis Zhang, Yihe Jiang, Bingjie Zhang, Pengyuan Chiu, Sung K. Lee, Meng H. Bone Joint Res Bone Biology AIMS: Tissue inhibitors of metalloproteinases (TIMPs) are the endogenous inhibitors of the zinc-dependent matrix metalloproteinases (MMP) and A disintegrin and metalloproteinases (ADAM) involved in extracellular matrix modulation. The present study aims to develop the TIMPs as biologics for osteoclast-related disorders. METHODS: We examine the inhibitory effect of a high affinity, glycosyl-phosphatidylinositol-anchored TIMP variant named ‘T1(PrαTACE)’ on receptor activator of nuclear factor kappa-Β ligand (RANKL)-induced osteoclast differentiation. RESULTS: Osteoclast progenitor cells transduced with T1(PrαTACE) failed to form tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts or exhibit bone-resorbing activity following treatment with RANKL. At the messenger RNA level, T1(PrαTACE) strongly attenuated expression of key osteoclast marker genes that included TRAP, cathepsin K, osteoclast stimulatory transmembrane protein (OC-STAMP), dendritic cell-specific transmembrane protein (DC-STAMP), osteoclast-associated receptor (OSCAR), and ATPase H(+)-transporting V0 subunit d2 (ATP6V0D2) by blocking autoamplification of nuclear factor of activated T cells 1 (NFATc1), the osteoclastogenic transcription factor. T1(PrαTACE) selectively extended p44/42 mitogen-activated protein kinase activation, an action that may have interrupted terminal differentiation of osteoclasts. Inhibition studies with broad-spectrum hydroxamate inhibitors confirmed that the anti-resorptive activity of T1(PrαTACE) was not reliant on its metalloproteinase-inhibitory activity. CONCLUSION: T1(PrαTACE) disrupts the RANKL-NFATc1 signalling pathway, which leads to osteoclast dysfunction. As a novel candidate in the prevention of osteoclastogenesis, the TIMP could potentially be developed for the treatment of osteoclast-related disorders such as osteoporosis. Cite this article: Bone Joint Res 2022;11(11):763–776. The British Editorial Society of Bone & Joint Surgery 2022-11-01 /pmc/articles/PMC9680204/ /pubmed/36331083 http://dx.doi.org/10.1302/2046-3758.1111.BJR-2022-0147.R2 Text en © 2022 Author(s) et al. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (CC BY-NC-ND 4.0) licence, which permits the copying and redistribution of the work only, and provided the original author and source are credited. See https://creativecommons.org/licenses/by-nc-nd/4.0/ |
spellingShingle | Bone Biology Zhang, Yihe Jiang, Bingjie Zhang, Pengyuan Chiu, Sung K. Lee, Meng H. Complete abrogation of key osteoclast markers with a membrane-anchored tissue inhibitor of metalloproteinase: a novel approach in the prevention of osteoclastogenesis |
title | Complete abrogation of key osteoclast markers with a membrane-anchored tissue inhibitor of metalloproteinase: a novel approach in the prevention of osteoclastogenesis |
title_full | Complete abrogation of key osteoclast markers with a membrane-anchored tissue inhibitor of metalloproteinase: a novel approach in the prevention of osteoclastogenesis |
title_fullStr | Complete abrogation of key osteoclast markers with a membrane-anchored tissue inhibitor of metalloproteinase: a novel approach in the prevention of osteoclastogenesis |
title_full_unstemmed | Complete abrogation of key osteoclast markers with a membrane-anchored tissue inhibitor of metalloproteinase: a novel approach in the prevention of osteoclastogenesis |
title_short | Complete abrogation of key osteoclast markers with a membrane-anchored tissue inhibitor of metalloproteinase: a novel approach in the prevention of osteoclastogenesis |
title_sort | complete abrogation of key osteoclast markers with a membrane-anchored tissue inhibitor of metalloproteinase: a novel approach in the prevention of osteoclastogenesis |
topic | Bone Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9680204/ https://www.ncbi.nlm.nih.gov/pubmed/36331083 http://dx.doi.org/10.1302/2046-3758.1111.BJR-2022-0147.R2 |
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