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Published on: July 6, 2022
Endochondral Growth Defect and Deployment of Transient Chondrocyte Behaviors Underlie Osteoarthritis Onset in a
K A Staines1, K Madi2, S M Mirczuk3
1Royal Veterinary College, University of London, London, UK, and Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, UK.
Objective:
To explore whether aberrant transient chondrocyte behaviors occur in the joints of STR/Ort mice (which spontaneously develop osteoarthritis [OA]) and whether they are attributable to an endochondral growth defect.
Methods:
Knee joints from STR/Ort mice with advanced OA and age-matched CBA (control) mice were examined by Affymetrix microarray profiling, multiplex polymerase chain reaction (PCR) analysis, and immunohistochemical labeling of endochondral markers, including sclerostin and MEPE. The endochondral phenotype of STR/Ort mice was analyzed by histologic examination, micro-computed tomography, and ex vivo organ culture. A novel protocol for quantifying bony bridges across the murine epiphysis (growth plate fusion) using synchrotron x-ray computed microtomography was developed and applied.
Results:
Meta-analysis of transcription profiles showed significant elevation in functions linked with endochondral ossification in STR/Ort mice (compared to CBA mice; P < 0.05). Consistent with this, immunolabeling revealed increased matrix metalloproteinase 13 (MMP-13) and type X collagen expression in STR/Ort mouse joints, and multiplex quantitative reverse transcriptase-PCR showed differential expression of known mineralization regulators, suggesting an inherent chondrocyte defect. Support for the notion of an endochondral defect included accelerated growth, increased zone of growth plate proliferative chondrocytes (P < 0.05), and widespread type X collagen/MMP-13 labeling beyond the expected hypertrophic zone distribution. OA development involved concomitant focal suppression of sclerostin/MEPE in STR/Ort mice. Our novel synchrotron radiation microtomography method showed increased numbers (P < 0.001) and mean areal growth plate bridge densities (P < 0.01) in young and aged STR/Ort mice compared to age-matched CBA mice.
Conclusion:
Taken together, our data support the notion of an inherent endochondral defect that is linked to growth dynamics and subject to regulation by the MEPE/sclerostin axis and may represent an underlying mechanism of pathologic ossification in OA.
Insights
STR/Ort mice exhibit an inherent endochondral growth defect, leading to aberrant chondrocyte behavior and pathological ossification in osteoarthritis (OA). This defect involves altered mineralization regulators and is influenced by the MEPE/sclerostin axis.
Area of Science:
- Orthopedics and Rheumatology
- Developmental Biology
- Biochemistry
Background:
- Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage breakdown and bone remodeling.
- Endochondral ossification is a critical process for bone development and growth, involving the transformation of cartilage into bone.
- Aberrant chondrocyte behavior and endochondral ossification defects are implicated in the pathogenesis of OA.
Purpose of the Study:
- To investigate aberrant chondrocyte behaviors in STR/Ort mice, a spontaneous osteoarthritis model.
- To determine if these chondrocyte behaviors are linked to an endochondral growth defect.
- To explore the role of the MEPE/sclerostin axis in OA pathogenesis.
Main Methods:
- Comparative analysis of knee joints from STR/Ort mice and control CBA mice using microarray profiling and multiplex PCR.
- Immunohistochemical labeling of endochondral markers (sclerostin, MEPE, MMP-13, type X collagen).
- Histologic examination, micro-computed tomography, and synchrotron X-ray computed microtomography to assess endochondral phenotype and growth plate fusion.
Main Results:
- STR/Ort mice showed elevated expression of genes related to endochondral ossification, including MMP-13 and type X collagen.
- Evidence of an endochondral defect included accelerated growth and increased proliferative chondrocytes.
- Novel microtomography method revealed increased bony bridges in STR/Ort mice, indicating impaired growth plate fusion.
Conclusions:
- An inherent endochondral defect, linked to growth dynamics, contributes to pathological ossification in OA.
- The MEPE/sclerostin axis plays a regulatory role in this process.
- These findings offer insights into the underlying mechanisms of OA development.
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