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Title: Comparative Transcriptomics Identifies Novel Genes and Pathways Involved in Post-Traumatic Osteoarthritis Development and Progression

Abstract

Anterior cruciate ligament (ACL) injuries often result in post-traumatic osteoarthritis (PTOA). To better understand the molecular mechanisms behind PTOA development following ACL injury, we profiled ACL injury-induced transcriptional changes in knee joints of three mouse strains with varying susceptibility to OA: STR/ort (highly susceptible), C57BL/6J (moderately susceptible) and super-healer MRL/MpJ (not susceptible). Right knee joints of the mice were injured using a non-invasive tibial compression injury model and global gene expression was quantified before and at 1-day, 1-week, and 2-weeks post-injury using RNA-seq. Following injury, injured and uninjured joints of STR/ort and injured C57BL/6J joints displayed significant cartilage degeneration while MRL/MpJ had little cartilage damage. Gene expression analysis suggested that prolonged inflammation and elevated catabolic activity in STR/ort injured joints, compared to the other two strains may be responsible for the severe PTOA phenotype observed in this strain. MRL/MpJ had the lowest expression values for several inflammatory cytokines and catabolic enzymes activated in response to ACL injury. Furthermore, we identified several genes highly expressed in MRL/MpJ compared to the other two strains including B4galnt2 and Tpsab1 which may contribute to enhanced healing in the MRL/MpJ. Overall, this study has increased our knowledge of early molecular changes associated with PTOA development.

Authors:
ORCiD logo [1];  [2];  [2];  [1];  [3];  [3];  [4];  [2]
  1. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Physical and Life Sciences Directorate
  2. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Physical and Life Sciences Directorate; Univ. of California, Merced, CA (United States). School of Natural Sciences
  3. Regeneron Pharmaceuticals, Tarrytown, NY (United States)
  4. UC Davis Medical Center, Sacramento, CA (United States). Dept. of Orthopedic Surgery
Publication Date:
Research Org.:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Univ. of California, Merced, CA (United States); UC Davis Medical Center, Sacramento, CA (United States)
Sponsoring Org.:
USDOE; USDOD; National Inst. of Health (NIH) (United States)
OSTI Identifier:
1476231
Report Number(s):
LLNL-JRNL-747404
Journal ID: ISSN 1422-0067; 932332
Grant/Contract Number:  
AC52-07NA27344; OR130220; AR062603
Resource Type:
Accepted Manuscript
Journal Name:
International Journal of Molecular Sciences (Online)
Additional Journal Information:
Journal Name: International Journal of Molecular Sciences (Online); Journal Volume: 19; Journal Issue: 9; Journal ID: ISSN 1422-0067
Publisher:
MDPI
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; osteoarthritis; RNA-seq; STR/ort; C57BL/6J; MRL/MpJ; ACL injury; PTOA; regeneration; inflammation; B4galnt2

Citation Formats

Sebastian, Aimy, Chang, Jiun, Mendez, Melanie, Murugesh, Deepa, Hatsell, Sarah, Economides, Aris, Christiansen, Blaine, and Loots, Gabriela. Comparative Transcriptomics Identifies Novel Genes and Pathways Involved in Post-Traumatic Osteoarthritis Development and Progression. United States: N. p., 2018. Web. doi:10.3390/ijms19092657.
Sebastian, Aimy, Chang, Jiun, Mendez, Melanie, Murugesh, Deepa, Hatsell, Sarah, Economides, Aris, Christiansen, Blaine, & Loots, Gabriela. Comparative Transcriptomics Identifies Novel Genes and Pathways Involved in Post-Traumatic Osteoarthritis Development and Progression. United States. doi:10.3390/ijms19092657.
Sebastian, Aimy, Chang, Jiun, Mendez, Melanie, Murugesh, Deepa, Hatsell, Sarah, Economides, Aris, Christiansen, Blaine, and Loots, Gabriela. Fri . "Comparative Transcriptomics Identifies Novel Genes and Pathways Involved in Post-Traumatic Osteoarthritis Development and Progression". United States. doi:10.3390/ijms19092657. https://www.osti.gov/servlets/purl/1476231.
@article{osti_1476231,
title = {Comparative Transcriptomics Identifies Novel Genes and Pathways Involved in Post-Traumatic Osteoarthritis Development and Progression},
author = {Sebastian, Aimy and Chang, Jiun and Mendez, Melanie and Murugesh, Deepa and Hatsell, Sarah and Economides, Aris and Christiansen, Blaine and Loots, Gabriela},
abstractNote = {Anterior cruciate ligament (ACL) injuries often result in post-traumatic osteoarthritis (PTOA). To better understand the molecular mechanisms behind PTOA development following ACL injury, we profiled ACL injury-induced transcriptional changes in knee joints of three mouse strains with varying susceptibility to OA: STR/ort (highly susceptible), C57BL/6J (moderately susceptible) and super-healer MRL/MpJ (not susceptible). Right knee joints of the mice were injured using a non-invasive tibial compression injury model and global gene expression was quantified before and at 1-day, 1-week, and 2-weeks post-injury using RNA-seq. Following injury, injured and uninjured joints of STR/ort and injured C57BL/6J joints displayed significant cartilage degeneration while MRL/MpJ had little cartilage damage. Gene expression analysis suggested that prolonged inflammation and elevated catabolic activity in STR/ort injured joints, compared to the other two strains may be responsible for the severe PTOA phenotype observed in this strain. MRL/MpJ had the lowest expression values for several inflammatory cytokines and catabolic enzymes activated in response to ACL injury. Furthermore, we identified several genes highly expressed in MRL/MpJ compared to the other two strains including B4galnt2 and Tpsab1 which may contribute to enhanced healing in the MRL/MpJ. Overall, this study has increased our knowledge of early molecular changes associated with PTOA development.},
doi = {10.3390/ijms19092657},
journal = {International Journal of Molecular Sciences (Online)},
number = 9,
volume = 19,
place = {United States},
year = {2018},
month = {9}
}

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