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Updated: May 13, 2026
Software-Assisted Quantitative Measurement of Osteoarthritic Subchondral Bone Thickness
Published on: March 18, 2022
Transcriptomics of wild-type mice and mice lacking ADAMTS-5 activity identifies genes involved in osteoarthritis
John F Bateman1, Lynn Rowley, Daniele Belluoccio
1Murdoch Childrens Research Institute and University of Melbourne, Parkville, Victoria, Australia. john.bateman@mcri.edu.au
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.
Insights
Researchers identified novel genes involved in osteoarthritis (OA) independent of ADAMTS-5 activity, offering new insights into OA mechanisms and potential therapeutic targets for cartilage degeneration.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage breakdown.
- Understanding the molecular mechanisms of OA is crucial for developing effective treatments.
- Gene expression changes play a significant role in OA pathogenesis.
Purpose of the Study:
- To identify gene expression changes in mice with osteoarthritis (OA).
- To explore the underlying mechanisms of OA pathogenesis.
- To distinguish OA-related gene expression changes independent of ADAMTS-5 activity.
Main Methods:
- Gene expression profiling was performed on cartilage from wild-type (WT) and Adamts5Δcat mice with surgically induced OA.
- Mechanical instability was induced via destabilization of the medial meniscus (DMM) in 10-week-old male mice.
- Cartilage samples were collected at 1, 2, and 6 weeks post-surgery for RNA extraction and microarray analysis.
Main Results:
- Several OA-related genes (e.g., Ptgs2, Phdla2, Il11) were up-regulated independently of ADAMTS-5 activity.
- Genes such as Col10a1 and Wnt/β-catenin pathway genes required ADAMTS-5 activity for altered expression.
- Cell death pathways and endoplasmic reticulum stress networks (Tp53, Foxo4, Xbp1) were activated.
- Novel cartilage proteases (Prss46, Klk8) were identified among up-regulated degradome genes.
Conclusions:
- Several genes with an ADAMTS-5-independent role in OA were identified as potential OA initiation candidates.
- This study provides novel insights into the sequence of gene dysregulation in OA.
- The findings contribute to understanding the molecular basis of cartilage destruction in OA.
