Osteomodulin down-regulation is associated with osteoarthritis development

Jérémie Zappia; Qiao Tong; Renee Van der Cruyssen; Frederique  Cornelis; Cécile Lambert; Tiago  Pinto Coelho; Juliane  Grisart; E Kague; Rik Lories; Marc Muller; Dirk Elewaut; Christina Hammond; Christelle  Sanchez; yves henrotin

doi:10.1038/s41413-023-00286-5

Osteomodulin down-regulation is associated with osteoarthritis development

Jérémie Zappia^*, Qiao Tong, Renee Van der Cruyssen, Frederique Cornelis, Cécile Lambert, Tiago Pinto Coelho, Juliane Grisart, E Kague, Rik Lories, Marc Muller , Dirk Elewaut, Christina Hammond, Christelle Sanchez, yves henrotin

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

3 Citations (Scopus)

Abstract

Abnormal subchondral bone remodeling leading to sclerosis is a main feature of osteoarthritis (OA) and Osteomodulin (OMD), a proteoglycan involved in extracellular matrix mineralization, is associated to the sclerotic phenotype. However, the functions of OMD remain poorly understood, specifically in vivo. We used knock-out and overexpressing male mice for Omd and mutant zebrafish to study its roles in bone and cartilage metabolism and in the development of OA. The expression of Omd is deeply correlated to bone and cartilage microarchitectures affecting the bone volume and the onset of subchondral bone sclerosis and spontaneous cartilage lesions. Mechanistically, OMD binds to RANKL and inhibits osteoclastogenesis; thus controlling the balance of the bone remodeling. In conclusions, OMD is a key factor in subchondral bone sclerosis associated with OA. It participates in bone and cartilage homeostasis acting on the regulation of osteoclastogenesis. Targeting OMD may be a promising new and personalized approach for OA.

Original language	English
Article number	49
Journal	Bone Research
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41413-023-00286-5
Publication status	Published - 20 Sept 2023

Bibliographical note

Funding Information:
The mutant mouse strain deficient for Omd used for this research project, C57BL/6 Omd/Mmucd, RRID: MMRRC_011749-UCD, was obtained from the Mutant Mouse Resource and Research Center (MMRRC) at the University of California at Davis, an NIH-funded strain repository, and was donated to the MMRRC by Lexicon Genetics Incorporated. The mutation targeted coding exons 1 and 2 by homologous recombination. The genotyping protocol from MMRRC was applied. The overexpressing mouse strain for Omd used for this research project, C57BL/6 Tg(Bglap-Omd)1Kieg, EMMA ID EM:02120, was obtained from the European Mouse Mutant Archive (EMMA), a repository supported by the national research programs and by the EC’s Research and Innovation program Horizon 2020. The transgenic line expressed Omd under the osteocalcin promoter in addition to its natural expression; hence, Omd overexpression was only osteoblast specific. Strains were crossed with WT C57BL/6 mice to maintain the line. Transgenic, WT, and mutant mice were maintained on a 12-h light/dark cycle with food and water supplied ad libitum. To simplify the nomenclature in the paper, we refer to the Omd-deficient mice as “KO” and to the Tg(Bglap-Omd) as “UP”. The ethics committee of the University of Liège approved all experimental procedures (reference no. 19-2090). tm1Lex

Funding Information:
The authors acknowledge the mouse facility of the University of Liege for the help provided during the housing as well as the zebrafish facility of the University of Liège and of Bristol. The authors acknowledge the GIGA University of Liège Genomic Next Generation Sequencing platform for having performed the RNA sequencing. The authors acknowledge the GIGA University of Liège Immunohistology platform and the Bristol University Histology platform for the help provided with the sample preparation. The authors acknowledge Prof. Stefan Schulte-Merker for kindly providing the transgenic zebrafish line TgBAC(ctsk:Citrine). The KU Leuven X-ray Computed Tomography Core facility is acknowledged for the 3D image acquisition and quantitative postprocessing tools ([ http://www.xct.kuleuven.be )] www.xct.kuleuven.be ). The Hercules fund of the FWO is acknowledged for their financial support of the project I013518N “The KU Leuven X-ray computed tomography center: a versatile and structured way to unravel the material structures and dynamic processes”. The authors acknowledge Carla Geeroms for her help during the X-ray computed tomography data acquisition. The authors acknowledge MaJEB sprl (Liège, Belgium) for their help provided with the biomechanical testing of the tibiae. The authors acknowledge Ratish Raman, Prescilia Centonze, Clémentine Lausberg, Lisa Carton and Laura Massoz for technical support. This work was funded by the F.R.S.-FNRS for the “EOS: The Excellence of Science-Join-t-against-Osteoarthritis”, grant number 30480119, by a research grant from the Osteoarthritis Foundation and by the University of Liege (Fonds Léon Fredericq and Fonds Speciaux à la Recherche). C.L.H., E.K. and Q.T. were funded by Versus Arthritis senior fellowship 21937. M.M. is a Maître de Recherche at the Fonds National de Recherche Scientifique (FNRS).

Funding Information:
The authors acknowledge the mouse facility of the University of Liege for the help provided during the housing as well as the zebrafish facility of the University of Liège and of Bristol. The authors acknowledge the GIGA University of Liège Genomic Next Generation Sequencing platform for having performed the RNA sequencing. The authors acknowledge the GIGA University of Liège Immunohistology platform and the Bristol University Histology platform for the help provided with the sample preparation. The authors acknowledge Prof. Stefan Schulte-Merker for kindly providing the transgenic zebrafish line TgBAC(ctsk:Citrine). The KU Leuven X-ray Computed Tomography Core facility is acknowledged for the 3D image acquisition and quantitative postprocessing tools ([http://www.xct.kuleuven.be)]www.xct.kuleuven.be). The Hercules fund of the FWO is acknowledged for their financial support of the project I013518N “The KU Leuven X-ray computed tomography center: a versatile and structured way to unravel the material structures and dynamic processes”. The authors acknowledge Carla Geeroms for her help during the X-ray computed tomography data acquisition. The authors acknowledge MaJEB sprl (Liège, Belgium) for their help provided with the biomechanical testing of the tibiae. The authors acknowledge Ratish Raman, Prescilia Centonze, Clémentine Lausberg, Lisa Carton and Laura Massoz for technical support. This work was funded by the F.R.S.-FNRS for the “EOS: The Excellence of Science-Join-t-against-Osteoarthritis”, grant number 30480119, by a research grant from the Osteoarthritis Foundation and by the University of Liege (Fonds Léon Fredericq and Fonds Speciaux à la Recherche). C.L.H., E.K. and Q.T. were funded by Versus Arthritis senior fellowship 21937. M.M. is a Maître de Recherche at the Fonds National de Recherche Scientifique (FNRS).

Publisher Copyright:
© 2023, West China School of Stomatology Sichuan University.

Keywords

osteomodulin
OSTEOARTHRITIS
CARTILAGE
SUBCHONDRAL BONE
osteoclast

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Cite this

@article{ed5837fef0a144caa61b957c5f4566be,

title = "Osteomodulin down-regulation is associated with osteoarthritis development",

abstract = "Abnormal subchondral bone remodeling leading to sclerosis is a main feature of osteoarthritis (OA) and Osteomodulin (OMD), a proteoglycan involved in extracellular matrix mineralization, is associated to the sclerotic phenotype. However, the functions of OMD remain poorly understood, specifically in vivo. We used knock-out and overexpressing male mice for Omd and mutant zebrafish to study its roles in bone and cartilage metabolism and in the development of OA. The expression of Omd is deeply correlated to bone and cartilage microarchitectures affecting the bone volume and the onset of subchondral bone sclerosis and spontaneous cartilage lesions. Mechanistically, OMD binds to RANKL and inhibits osteoclastogenesis; thus controlling the balance of the bone remodeling. In conclusions, OMD is a key factor in subchondral bone sclerosis associated with OA. It participates in bone and cartilage homeostasis acting on the regulation of osteoclastogenesis. Targeting OMD may be a promising new and personalized approach for OA.",

keywords = "osteomodulin, OSTEOARTHRITIS, CARTILAGE, SUBCHONDRAL BONE, osteoclast",

author = "J{\'e}r{\'e}mie Zappia and Qiao Tong and {Van der Cruyssen}, Renee and Frederique Cornelis and C{\'e}cile Lambert and {Pinto Coelho}, Tiago and Juliane Grisart and E Kague and Rik Lories and Marc Muller and Dirk Elewaut and Christina Hammond and Christelle Sanchez and yves henrotin",

note = "Funding Information: The mutant mouse strain deficient for Omd used for this research project, C57BL/6 Omd/Mmucd, RRID: MMRRC_011749-UCD, was obtained from the Mutant Mouse Resource and Research Center (MMRRC) at the University of California at Davis, an NIH-funded strain repository, and was donated to the MMRRC by Lexicon Genetics Incorporated. The mutation targeted coding exons 1 and 2 by homologous recombination. The genotyping protocol from MMRRC was applied. The overexpressing mouse strain for Omd used for this research project, C57BL/6 Tg(Bglap-Omd)1Kieg, EMMA ID EM:02120, was obtained from the European Mouse Mutant Archive (EMMA), a repository supported by the national research programs and by the EC{\textquoteright}s Research and Innovation program Horizon 2020. The transgenic line expressed Omd under the osteocalcin promoter in addition to its natural expression; hence, Omd overexpression was only osteoblast specific. Strains were crossed with WT C57BL/6 mice to maintain the line. Transgenic, WT, and mutant mice were maintained on a 12-h light/dark cycle with food and water supplied ad libitum. To simplify the nomenclature in the paper, we refer to the Omd-deficient mice as “KO” and to the Tg(Bglap-Omd) as “UP”. The ethics committee of the University of Li{\`e}ge approved all experimental procedures (reference no. 19-2090). tm1Lex Funding Information: The authors acknowledge the mouse facility of the University of Liege for the help provided during the housing as well as the zebrafish facility of the University of Li{\`e}ge and of Bristol. The authors acknowledge the GIGA University of Li{\`e}ge Genomic Next Generation Sequencing platform for having performed the RNA sequencing. The authors acknowledge the GIGA University of Li{\`e}ge Immunohistology platform and the Bristol University Histology platform for the help provided with the sample preparation. The authors acknowledge Prof. Stefan Schulte-Merker for kindly providing the transgenic zebrafish line TgBAC(ctsk:Citrine). The KU Leuven X-ray Computed Tomography Core facility is acknowledged for the 3D image acquisition and quantitative postprocessing tools ([ http://www.xct.kuleuven.be )] www.xct.kuleuven.be ). The Hercules fund of the FWO is acknowledged for their financial support of the project I013518N “The KU Leuven X-ray computed tomography center: a versatile and structured way to unravel the material structures and dynamic processes”. The authors acknowledge Carla Geeroms for her help during the X-ray computed tomography data acquisition. The authors acknowledge MaJEB sprl (Li{\`e}ge, Belgium) for their help provided with the biomechanical testing of the tibiae. The authors acknowledge Ratish Raman, Prescilia Centonze, Cl{\'e}mentine Lausberg, Lisa Carton and Laura Massoz for technical support. This work was funded by the F.R.S.-FNRS for the “EOS: The Excellence of Science-Join-t-against-Osteoarthritis”, grant number 30480119, by a research grant from the Osteoarthritis Foundation and by the University of Liege (Fonds L{\'e}on Fredericq and Fonds Speciaux {\`a} la Recherche). C.L.H., E.K. and Q.T. were funded by Versus Arthritis senior fellowship 21937. M.M. is a Ma{\^i}tre de Recherche at the Fonds National de Recherche Scientifique (FNRS). Funding Information: The authors acknowledge the mouse facility of the University of Liege for the help provided during the housing as well as the zebrafish facility of the University of Li{\`e}ge and of Bristol. The authors acknowledge the GIGA University of Li{\`e}ge Genomic Next Generation Sequencing platform for having performed the RNA sequencing. The authors acknowledge the GIGA University of Li{\`e}ge Immunohistology platform and the Bristol University Histology platform for the help provided with the sample preparation. The authors acknowledge Prof. Stefan Schulte-Merker for kindly providing the transgenic zebrafish line TgBAC(ctsk:Citrine). The KU Leuven X-ray Computed Tomography Core facility is acknowledged for the 3D image acquisition and quantitative postprocessing tools ([http://www.xct.kuleuven.be)]www.xct.kuleuven.be). The Hercules fund of the FWO is acknowledged for their financial support of the project I013518N “The KU Leuven X-ray computed tomography center: a versatile and structured way to unravel the material structures and dynamic processes”. The authors acknowledge Carla Geeroms for her help during the X-ray computed tomography data acquisition. The authors acknowledge MaJEB sprl (Li{\`e}ge, Belgium) for their help provided with the biomechanical testing of the tibiae. The authors acknowledge Ratish Raman, Prescilia Centonze, Cl{\'e}mentine Lausberg, Lisa Carton and Laura Massoz for technical support. This work was funded by the F.R.S.-FNRS for the “EOS: The Excellence of Science-Join-t-against-Osteoarthritis”, grant number 30480119, by a research grant from the Osteoarthritis Foundation and by the University of Liege (Fonds L{\'e}on Fredericq and Fonds Speciaux {\`a} la Recherche). C.L.H., E.K. and Q.T. were funded by Versus Arthritis senior fellowship 21937. M.M. is a Ma{\^i}tre de Recherche at the Fonds National de Recherche Scientifique (FNRS). Publisher Copyright: {\textcopyright} 2023, West China School of Stomatology Sichuan University.",

year = "2023",

month = sep,

day = "20",

doi = "10.1038/s41413-023-00286-5",

language = "English",

volume = "11",

journal = "Bone Research",

issn = "2095-6231",

publisher = "Springer Nature",

number = "1",

}

TY - JOUR

T1 - Osteomodulin down-regulation is associated with osteoarthritis development

AU - Zappia, Jérémie

AU - Tong, Qiao

AU - Van der Cruyssen, Renee

AU - Cornelis, Frederique

AU - Lambert, Cécile

AU - Pinto Coelho, Tiago

AU - Grisart, Juliane

AU - Kague, E

AU - Lories, Rik

AU - Muller , Marc

AU - Elewaut, Dirk

AU - Hammond, Christina

AU - Sanchez, Christelle

AU - henrotin, yves

N1 - Funding Information: The mutant mouse strain deficient for Omd used for this research project, C57BL/6 Omd/Mmucd, RRID: MMRRC_011749-UCD, was obtained from the Mutant Mouse Resource and Research Center (MMRRC) at the University of California at Davis, an NIH-funded strain repository, and was donated to the MMRRC by Lexicon Genetics Incorporated. The mutation targeted coding exons 1 and 2 by homologous recombination. The genotyping protocol from MMRRC was applied. The overexpressing mouse strain for Omd used for this research project, C57BL/6 Tg(Bglap-Omd)1Kieg, EMMA ID EM:02120, was obtained from the European Mouse Mutant Archive (EMMA), a repository supported by the national research programs and by the EC’s Research and Innovation program Horizon 2020. The transgenic line expressed Omd under the osteocalcin promoter in addition to its natural expression; hence, Omd overexpression was only osteoblast specific. Strains were crossed with WT C57BL/6 mice to maintain the line. Transgenic, WT, and mutant mice were maintained on a 12-h light/dark cycle with food and water supplied ad libitum. To simplify the nomenclature in the paper, we refer to the Omd-deficient mice as “KO” and to the Tg(Bglap-Omd) as “UP”. The ethics committee of the University of Liège approved all experimental procedures (reference no. 19-2090). tm1Lex Funding Information: The authors acknowledge the mouse facility of the University of Liege for the help provided during the housing as well as the zebrafish facility of the University of Liège and of Bristol. The authors acknowledge the GIGA University of Liège Genomic Next Generation Sequencing platform for having performed the RNA sequencing. The authors acknowledge the GIGA University of Liège Immunohistology platform and the Bristol University Histology platform for the help provided with the sample preparation. The authors acknowledge Prof. Stefan Schulte-Merker for kindly providing the transgenic zebrafish line TgBAC(ctsk:Citrine). The KU Leuven X-ray Computed Tomography Core facility is acknowledged for the 3D image acquisition and quantitative postprocessing tools ([ http://www.xct.kuleuven.be )] www.xct.kuleuven.be ). The Hercules fund of the FWO is acknowledged for their financial support of the project I013518N “The KU Leuven X-ray computed tomography center: a versatile and structured way to unravel the material structures and dynamic processes”. The authors acknowledge Carla Geeroms for her help during the X-ray computed tomography data acquisition. The authors acknowledge MaJEB sprl (Liège, Belgium) for their help provided with the biomechanical testing of the tibiae. The authors acknowledge Ratish Raman, Prescilia Centonze, Clémentine Lausberg, Lisa Carton and Laura Massoz for technical support. This work was funded by the F.R.S.-FNRS for the “EOS: The Excellence of Science-Join-t-against-Osteoarthritis”, grant number 30480119, by a research grant from the Osteoarthritis Foundation and by the University of Liege (Fonds Léon Fredericq and Fonds Speciaux à la Recherche). C.L.H., E.K. and Q.T. were funded by Versus Arthritis senior fellowship 21937. M.M. is a Maître de Recherche at the Fonds National de Recherche Scientifique (FNRS). Funding Information: The authors acknowledge the mouse facility of the University of Liege for the help provided during the housing as well as the zebrafish facility of the University of Liège and of Bristol. The authors acknowledge the GIGA University of Liège Genomic Next Generation Sequencing platform for having performed the RNA sequencing. The authors acknowledge the GIGA University of Liège Immunohistology platform and the Bristol University Histology platform for the help provided with the sample preparation. The authors acknowledge Prof. Stefan Schulte-Merker for kindly providing the transgenic zebrafish line TgBAC(ctsk:Citrine). The KU Leuven X-ray Computed Tomography Core facility is acknowledged for the 3D image acquisition and quantitative postprocessing tools ([http://www.xct.kuleuven.be)]www.xct.kuleuven.be). The Hercules fund of the FWO is acknowledged for their financial support of the project I013518N “The KU Leuven X-ray computed tomography center: a versatile and structured way to unravel the material structures and dynamic processes”. The authors acknowledge Carla Geeroms for her help during the X-ray computed tomography data acquisition. The authors acknowledge MaJEB sprl (Liège, Belgium) for their help provided with the biomechanical testing of the tibiae. The authors acknowledge Ratish Raman, Prescilia Centonze, Clémentine Lausberg, Lisa Carton and Laura Massoz for technical support. This work was funded by the F.R.S.-FNRS for the “EOS: The Excellence of Science-Join-t-against-Osteoarthritis”, grant number 30480119, by a research grant from the Osteoarthritis Foundation and by the University of Liege (Fonds Léon Fredericq and Fonds Speciaux à la Recherche). C.L.H., E.K. and Q.T. were funded by Versus Arthritis senior fellowship 21937. M.M. is a Maître de Recherche at the Fonds National de Recherche Scientifique (FNRS). Publisher Copyright: © 2023, West China School of Stomatology Sichuan University.

PY - 2023/9/20

Y1 - 2023/9/20

N2 - Abnormal subchondral bone remodeling leading to sclerosis is a main feature of osteoarthritis (OA) and Osteomodulin (OMD), a proteoglycan involved in extracellular matrix mineralization, is associated to the sclerotic phenotype. However, the functions of OMD remain poorly understood, specifically in vivo. We used knock-out and overexpressing male mice for Omd and mutant zebrafish to study its roles in bone and cartilage metabolism and in the development of OA. The expression of Omd is deeply correlated to bone and cartilage microarchitectures affecting the bone volume and the onset of subchondral bone sclerosis and spontaneous cartilage lesions. Mechanistically, OMD binds to RANKL and inhibits osteoclastogenesis; thus controlling the balance of the bone remodeling. In conclusions, OMD is a key factor in subchondral bone sclerosis associated with OA. It participates in bone and cartilage homeostasis acting on the regulation of osteoclastogenesis. Targeting OMD may be a promising new and personalized approach for OA.

AB - Abnormal subchondral bone remodeling leading to sclerosis is a main feature of osteoarthritis (OA) and Osteomodulin (OMD), a proteoglycan involved in extracellular matrix mineralization, is associated to the sclerotic phenotype. However, the functions of OMD remain poorly understood, specifically in vivo. We used knock-out and overexpressing male mice for Omd and mutant zebrafish to study its roles in bone and cartilage metabolism and in the development of OA. The expression of Omd is deeply correlated to bone and cartilage microarchitectures affecting the bone volume and the onset of subchondral bone sclerosis and spontaneous cartilage lesions. Mechanistically, OMD binds to RANKL and inhibits osteoclastogenesis; thus controlling the balance of the bone remodeling. In conclusions, OMD is a key factor in subchondral bone sclerosis associated with OA. It participates in bone and cartilage homeostasis acting on the regulation of osteoclastogenesis. Targeting OMD may be a promising new and personalized approach for OA.

KW - osteomodulin

KW - OSTEOARTHRITIS

KW - CARTILAGE

KW - SUBCHONDRAL BONE

KW - osteoclast

U2 - 10.1038/s41413-023-00286-5

DO - 10.1038/s41413-023-00286-5

M3 - Article (Academic Journal)

C2 - 37730805

SN - 2095-6231

VL - 11

JO - Bone Research

JF - Bone Research

IS - 1

M1 - 49

ER -

Osteomodulin down-regulation is associated with osteoarthritis development

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