Tags

Type your tag names separated by a space and hit enter

Transcriptomics of wild-type mice and mice lacking ADAMTS-5 activity identifies genes involved in osteoarthritis initiation and cartilage destruction.
Arthritis Rheum. 2013 Jun; 65(6):1547-60.AR

Abstract

OBJECTIVE

To identify changes in gene expression in mice with osteoarthritis (OA) in order to explore the mechanisms of the disease.

METHODS

Gene expression profiling was performed in cartilage from mice with surgically induced OA. We used wild-type (WT) mice and Adamts5Δcat mice, in which ADAMTS-5 activity is lacking and aggrecan loss and cartilage erosion are inhibited, to distinguish gene expression changes that are independent of ADAMTS-5 activity and cartilage breakdown. Mechanical instability was introduced into the knee joints of 10-week-old male mice via surgical destabilization of the medial meniscus (DMM). Cartilage from the developing lesion in the destabilized medial meniscus and corresponding regions in sham-operated joints was harvested by microdissection at 1, 2, and 6 weeks postsurgery, and RNA was extracted, amplified, and hybridized to whole-genome microarrays.

RESULTS

Several previously identified OA-related genes, including Ptgs2, Crlf1, and Inhba, and novel genes, such as Phdla2 and Il11, were up-regulated in both WT mice and Adamts5Δcat mice, indicating that they are independent of ADAMTS-5 activity. The altered expression of other genes, including Col10a1, the sentinel marker of cartilage hypertrophy, and Wnt/β-catenin pathway genes, required ADAMTS-5 activity. Cell death pathway genes were dysregulated, and Tp53, Foxo4, and Xbp1 endoplasmic reticulum-stress transcriptional networks were activated. Analysis of degradome genes identified up-regulation of many proteases, including Mmp3, Capn2, and the novel cartilage proteases Prss46 and Klk8. Comparison with other studies identified 16 genes also dysregulated in rat and human OA as priorities for study.

CONCLUSION

We have identified, for the first time, several genes that have an ADAMTS-5-independent role in OA, identifying them as possible OA initiation candidates. This work provides new insights into the sequence of gene dysregulation and the molecular basis of cartilage destruction in OA.

Links

Aggregator Full Text

Authors+Show Affiliations

Bateman JF
Murdoch Childrens Research Institute and University of Melbourne, Parkville, Victoria, Australia. john.bateman@mcri.edu.au
Rowley L
No affiliation info available
Belluoccio D
No affiliation info available
Chan B
No affiliation info available
Bell K
No affiliation info available
Fosang AJ
No affiliation info available
Little CB
No affiliation info available

MeSH

ADAM ProteinsADAMTS5 ProteinAnimalsCartilage, ArticularGene Expression ProfilingMaleMiceMice, Inbred C57BLOsteoarthritisTranscriptome

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23436205

Citation

Bateman, John F., et al. "Transcriptomics of Wild-type Mice and Mice Lacking ADAMTS-5 Activity Identifies Genes Involved in Osteoarthritis Initiation and Cartilage Destruction." Arthritis and Rheumatism, vol. 65, no. 6, 2013, pp. 1547-60.
Bateman JF, Rowley L, Belluoccio D, et al. Transcriptomics of wild-type mice and mice lacking ADAMTS-5 activity identifies genes involved in osteoarthritis initiation and cartilage destruction. Arthritis Rheum. 2013;65(6):1547-60.
Bateman, J. F., Rowley, L., Belluoccio, D., Chan, B., Bell, K., Fosang, A. J., & Little, C. B. (2013). Transcriptomics of wild-type mice and mice lacking ADAMTS-5 activity identifies genes involved in osteoarthritis initiation and cartilage destruction. Arthritis and Rheumatism, 65(6), 1547-60. https://doi.org/10.1002/art.37900
Bateman JF, et al. Transcriptomics of Wild-type Mice and Mice Lacking ADAMTS-5 Activity Identifies Genes Involved in Osteoarthritis Initiation and Cartilage Destruction. Arthritis Rheum. 2013;65(6):1547-60. PubMed PMID: 23436205.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Transcriptomics of wild-type mice and mice lacking ADAMTS-5 activity identifies genes involved in osteoarthritis initiation and cartilage destruction. AU - Bateman,John F, AU - Rowley,Lynn, AU - Belluoccio,Daniele, AU - Chan,Ben, AU - Bell,Katrina, AU - Fosang,Amanda J, AU - Little,Christopher B, PY - 2012/08/28/received PY - 2013/02/05/accepted PY - 2013/2/26/entrez PY - 2013/2/26/pubmed PY - 2013/8/14/medline SP - 1547 EP - 60 JF - Arthritis and rheumatism JO - Arthritis Rheum VL - 65 IS - 6 N2 - OBJECTIVE: To identify changes in gene expression in mice with osteoarthritis (OA) in order to explore the mechanisms of the disease. METHODS: Gene expression profiling was performed in cartilage from mice with surgically induced OA. We used wild-type (WT) mice and Adamts5Δcat mice, in which ADAMTS-5 activity is lacking and aggrecan loss and cartilage erosion are inhibited, to distinguish gene expression changes that are independent of ADAMTS-5 activity and cartilage breakdown. Mechanical instability was introduced into the knee joints of 10-week-old male mice via surgical destabilization of the medial meniscus (DMM). Cartilage from the developing lesion in the destabilized medial meniscus and corresponding regions in sham-operated joints was harvested by microdissection at 1, 2, and 6 weeks postsurgery, and RNA was extracted, amplified, and hybridized to whole-genome microarrays. RESULTS: Several previously identified OA-related genes, including Ptgs2, Crlf1, and Inhba, and novel genes, such as Phdla2 and Il11, were up-regulated in both WT mice and Adamts5Δcat mice, indicating that they are independent of ADAMTS-5 activity. The altered expression of other genes, including Col10a1, the sentinel marker of cartilage hypertrophy, and Wnt/β-catenin pathway genes, required ADAMTS-5 activity. Cell death pathway genes were dysregulated, and Tp53, Foxo4, and Xbp1 endoplasmic reticulum-stress transcriptional networks were activated. Analysis of degradome genes identified up-regulation of many proteases, including Mmp3, Capn2, and the novel cartilage proteases Prss46 and Klk8. Comparison with other studies identified 16 genes also dysregulated in rat and human OA as priorities for study. CONCLUSION: We have identified, for the first time, several genes that have an ADAMTS-5-independent role in OA, identifying them as possible OA initiation candidates. This work provides new insights into the sequence of gene dysregulation and the molecular basis of cartilage destruction in OA. SN - 1529-0131 UR - https://www.unboundmedicine.com/medline/citation/23436205/Transcriptomics_of_wild_type_mice_and_mice_lacking_ADAMTS_5_activity_identifies_genes_involved_in_osteoarthritis_initiation_and_cartilage_destruction_ L2 - https://doi.org/10.1002/art.37900 DB - PRIME DP - Unbound Medicine ER -