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Abstract

Acute full thickness joint surface defects can undergo repair, which involves tissue patterning and endochondral bone formation. Molecular signals regulating this process may contribute to the repair outcome, chronic evolution and, eventually, the onset of osteoarthritis. We tested the hypothesis that mechanical injury modulates morphogenetic pathways in adult human articular cartilage explants. Adjacent articular cartilage explants were obtained from preserved areas of the femoral condyles of patients undergoing arthroplasty for osteoarthritis, or from a normal joint of a patient undergoing lower limb amputation. Paired explants were individually maintained in explant culture. From each pair, one explant was mechanically injured and the other left uninjured as a control. Cultures were terminated at different time points for histochemistry, immunohistochemistry and gene expression analysis by reverse transcription real time PCR. Bone morphogenetic protein 2 (BMP-2) mRNA was upregulated in the injured explants. We detected phosphorylation of SMAD-1 and SMAD-5, consistent with activation of the bone morphogenetic protein (BMP) pathway. FRZB-1 mRNA was downregulated in the injured explants, suggesting de-repression of WNT signaling. Accordingly, expression of the canonical WNT target genes Axin-2 and c-JUN was upregulated in the injured explants. Activation of the canonical WNT signaling pathway by LiCl treatment induced upregulation of COL2A1 and Aggrecan mRNA, suggesting an anabolic effect. Phosphorylation of SMAD-1/-5 and downregulation of FRZB were confirmed in vivo in a mouse model of joint surface injury. Taken together, these data show modulation of the BMP and WNT pathways following mechanical injury in vitro and in vivo, which may play a role in the reparative response of the joint surface. These pathways may, therefore, represent potential targets in protocols of biological joint surface defect repair.

GDF5 reduces MMP13 expression in human chondrocytes via DKK1 mediated canonical Wnt signaling inhibition

“…The differences to our study could be that our stimulation continued for a longer period of time and that our cells were retrieved from younger patients. Furthermore, in a study by Dell'Accio et al 11 , acute trauma was shown to increase levels of Wnt and Wnt associated proteins. The trauma also induced MMP13 expression in human cartilage explants.…”

Bone mineral density and prevalent osteoarthritis of the hip in older men for the Osteoporotic Fractures in Men (MrOS) Study Group

“…There is evidence from animal studies that wnt signaling has different effects on cartilage compared to bone (24, 25). Higher serum levels of the wnt antagonist Dickoff-1 (Dkk-1) have been found to be protective against the progression of RHOA in older women (26) and secreted frizzle-related protein 3 (sFRP-3), another wnt antagonist, may be protective against cartilage injury (26, 27). These results are intriguing, and the role of wnt signaling in cartilage and bone in relation to the osteophytic and atrophic phenotypes requires further study.…”

β-Catenin/T-cell Factor Signaling Is Activated during Lung Injury and Promotes the Survival and Migration of Alveolar Epithelial Cells

“…5B, MDCK cells). We reasoned that the isolation and short term culturing of rat AT2 cells may represent a form of cell/tissue injury and that activation of Wnt/␤-catenin signaling might accompany that injury, as previously indicated (45)(46)(47)(48). To address this, we used an established mouse model of alveolar epithelial cell injury by intratracheal administration of bleomycin (33) and sought evidence for canonical Wnt pathway activation by monitoring expression levels of the immediate early target gene, AXIN2.…”