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Published on: May 6, 2020
Inverse relationship between matrix remodeling and lipid metabolism during osteoarthritis progression in the STR/Ort
James W Watters1, Chun Cheng, Maureen Pickarski
1Merck, West Point, Pennsylvania, USA.
Objective:
The biologic changes associated with osteoarthritis (OA) are incompletely understood. The aim of this study was to elucidate the molecular mechanisms underlying OA progression in an STR/Ort murine model of spontaneous disease.
Methods:
Global patterns of gene expression were assessed using microarray analysis of articular cartilage/subchondral bone from the tibial plateaus of STR/Ort mice at 3, 9, and 12 months of age. The age-dependent severity of osteophyte formation and extent of cartilage damage were determined in the corresponding femurs using microfocal computed tomography and the Mankin histologic scoring system. Pathway analysis was used to identify the functions of genes associated with OA progression, and changes in gene expression were confirmed using immunohistochemistry.
Results:
Six hundred twenty-one genes were associated with both osteophyte formation and cartilage damage in the STR/Ort joints. Genes involved in the development/function of connective tissue and in lipid metabolism were most significantly enriched and regulated during disease progression. Genes directly interacting with peroxisome proliferator-activated receptor alpha (PPARalpha)/PPARgamma were down-regulated, whereas those genes involved with connective tissue remodeling were up-regulated during disease progression. Associations of down-regulation of myotubularin-related phosphatase 1 (a phosphoinositide 3-phosphatase involved in lipid signaling) and up-regulation of biglycan (a member of the small leucine-rich protein family known to modulate osteoblast differentiation and matrix mineralization) with OA progression were confirmed by immunohistochemistry.
Conclusion:
Since adipogenesis and osteogenesis are inversely related in the developing skeletal tissue, these results suggest that a shift in the differentiation of mesenchymal cells from adipogenesis toward osteogenesis is a component of the OA pathophysiologic processes occurring in the tibial plateau joints of STR/Ort mice.
Insights
Osteoarthritis progression involves connective tissue remodeling and altered lipid metabolism. Mesenchymal stem cell differentiation shifts from fat to bone formation, contributing to OA in mouse joints.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- Osteoarthritis (OA) pathogenesis involves complex molecular changes that are not fully understood.
- Investigating spontaneous OA models is crucial for uncovering underlying biological mechanisms.
Purpose of the Study:
- To elucidate the molecular mechanisms driving osteoarthritis progression.
- To analyze age-dependent gene expression patterns in a spontaneous murine OA model (STR/Ort).
Main Methods:
- Microarray analysis of articular cartilage and subchondral bone from STR/Ort mice at 3, 9, and 12 months.
- Microfocal computed tomography and Mankin scoring for assessing osteophyte formation and cartilage damage.
- Pathway analysis, immunohistochemistry to confirm gene expression changes.
Main Results:
- Identified 621 genes associated with osteophyte formation and cartilage damage in OA joints.
- Highlighted enrichment of genes in connective tissue development/function and lipid metabolism.
- Observed down-regulation of PPARalpha/PPARgamma interacting genes and up-regulation of connective tissue remodeling genes.
Conclusions:
- Suggests a shift in mesenchymal stem cell differentiation from adipogenesis to osteogenesis in OA.
- This differentiation shift is a key pathophysiological process in the tibial plateau joints of STR/Ort mice.
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