Transcriptome profiling of osteoblasts in a medaka (oryzias latipes) osteoporosis model identifies mmp13b as crucial for osteoclast activation

Matrix metalloproteases (MMPs) play crucial roles in extracellular matrix (ECM) modulation during osteoclast-driven bone remodeling. In the present study, we used transcriptome profiling of bone cells in a medaka model for osteoporosis and bone regeneration to identify factors critical for bone remo...

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Main Authors: Liu, Ranran, Imangali, Nurgul, Ethiraj, Lalith P., Carney, Tom J., Winkler, Christoph
Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
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Language:English
Published: 2022
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Online Access:https://hdl.handle.net/10356/163184
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spelling sg-ntu-dr.10356-1631842023-03-05T16:52:33Z Transcriptome profiling of osteoblasts in a medaka (oryzias latipes) osteoporosis model identifies mmp13b as crucial for osteoclast activation Liu, Ranran Imangali, Nurgul Ethiraj, Lalith P. Carney, Tom J. Winkler, Christoph Lee Kong Chian School of Medicine (LKCMedicine) Science::Medicine Osteoblasts Matrix Metalloprotease Matrix metalloproteases (MMPs) play crucial roles in extracellular matrix (ECM) modulation during osteoclast-driven bone remodeling. In the present study, we used transcriptome profiling of bone cells in a medaka model for osteoporosis and bone regeneration to identify factors critical for bone remodeling and homeostasis. This identified mmp13b, which was strongly expressed in osteoblast progenitors and upregulated under osteoporotic conditions and during regeneration of bony fin rays. To characterize the role of mmp13b in bone remodeling, we generated medaka mmp13b mutants by CRISPR/Cas9. We found that mmp13b mutants form normal numbers of osteoblasts and osteoclasts. However, osteoclast activity was severely impaired under osteoporotic conditions. In mmp13b mutants and embryos treated with the MMP13 inhibitor CL-82198, unmineralized collagens and mineralized bone matrix failed to be degraded. In addition, the dynamic migratory behavior of activated osteoclasts was severely affected in mmp13b mutants. Expression analysis showed that maturation genes were downregulated in mmp13b deficient osteoclasts suggesting that they remain in an immature and non-activated state. We also found that fin regeneration was delayed in mmp13b mutants with a concomitant alteration of the ECM and reduced numbers of osteoblast progenitors in regenerating joint regions. Together, our findings suggest that osteoblast-derived Mmp13b alters the bone ECM to allow the maturation and activation of osteoclasts during bone remodeling in a paracrine manner. Mmp13b-induced ECM alterations are also required to facilitate osteoblast progenitor recruitment and full regeneration of bony fin rays. Ministry of Education (MOE) National Research Foundation (NRF) Published version This project is supported by grants from the Singapore Ministry of Education (No. MOE2016-T2-2-086) and the National Research Foundation Singapore (NRF; NRF2017-NRF-ISF002-2671). 2022-11-28T06:00:00Z 2022-11-28T06:00:00Z 2022 Journal Article Liu, R., Imangali, N., Ethiraj, L. P., Carney, T. J. & Winkler, C. (2022). Transcriptome profiling of osteoblasts in a medaka (oryzias latipes) osteoporosis model identifies mmp13b as crucial for osteoclast activation. Frontiers in Cell and Developmental Biology, 10, 775512-. https://dx.doi.org/10.3389/fcell.2022.775512 2296-634X https://hdl.handle.net/10356/163184 10.3389/fcell.2022.775512 35281094 2-s2.0-85126235093 10 775512 en MOE2016-T2-2-086 NRF2017-NRF-ISF002-2671 Frontiers in Cell and Developmental Biology © 2022 Liu, Imangali, Ethiraj, Carney and Winkler. This is an openaccess article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Medicine
Osteoblasts
Matrix Metalloprotease
spellingShingle Science::Medicine
Osteoblasts
Matrix Metalloprotease
Liu, Ranran
Imangali, Nurgul
Ethiraj, Lalith P.
Carney, Tom J.
Winkler, Christoph
Transcriptome profiling of osteoblasts in a medaka (oryzias latipes) osteoporosis model identifies mmp13b as crucial for osteoclast activation
description Matrix metalloproteases (MMPs) play crucial roles in extracellular matrix (ECM) modulation during osteoclast-driven bone remodeling. In the present study, we used transcriptome profiling of bone cells in a medaka model for osteoporosis and bone regeneration to identify factors critical for bone remodeling and homeostasis. This identified mmp13b, which was strongly expressed in osteoblast progenitors and upregulated under osteoporotic conditions and during regeneration of bony fin rays. To characterize the role of mmp13b in bone remodeling, we generated medaka mmp13b mutants by CRISPR/Cas9. We found that mmp13b mutants form normal numbers of osteoblasts and osteoclasts. However, osteoclast activity was severely impaired under osteoporotic conditions. In mmp13b mutants and embryos treated with the MMP13 inhibitor CL-82198, unmineralized collagens and mineralized bone matrix failed to be degraded. In addition, the dynamic migratory behavior of activated osteoclasts was severely affected in mmp13b mutants. Expression analysis showed that maturation genes were downregulated in mmp13b deficient osteoclasts suggesting that they remain in an immature and non-activated state. We also found that fin regeneration was delayed in mmp13b mutants with a concomitant alteration of the ECM and reduced numbers of osteoblast progenitors in regenerating joint regions. Together, our findings suggest that osteoblast-derived Mmp13b alters the bone ECM to allow the maturation and activation of osteoclasts during bone remodeling in a paracrine manner. Mmp13b-induced ECM alterations are also required to facilitate osteoblast progenitor recruitment and full regeneration of bony fin rays.
author2 Lee Kong Chian School of Medicine (LKCMedicine)
author_facet Lee Kong Chian School of Medicine (LKCMedicine)
Liu, Ranran
Imangali, Nurgul
Ethiraj, Lalith P.
Carney, Tom J.
Winkler, Christoph
format Article
author Liu, Ranran
Imangali, Nurgul
Ethiraj, Lalith P.
Carney, Tom J.
Winkler, Christoph
author_sort Liu, Ranran
title Transcriptome profiling of osteoblasts in a medaka (oryzias latipes) osteoporosis model identifies mmp13b as crucial for osteoclast activation
title_short Transcriptome profiling of osteoblasts in a medaka (oryzias latipes) osteoporosis model identifies mmp13b as crucial for osteoclast activation
title_full Transcriptome profiling of osteoblasts in a medaka (oryzias latipes) osteoporosis model identifies mmp13b as crucial for osteoclast activation
title_fullStr Transcriptome profiling of osteoblasts in a medaka (oryzias latipes) osteoporosis model identifies mmp13b as crucial for osteoclast activation
title_full_unstemmed Transcriptome profiling of osteoblasts in a medaka (oryzias latipes) osteoporosis model identifies mmp13b as crucial for osteoclast activation
title_sort transcriptome profiling of osteoblasts in a medaka (oryzias latipes) osteoporosis model identifies mmp13b as crucial for osteoclast activation
publishDate 2022
url https://hdl.handle.net/10356/163184
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