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Reduced EGFR signaling enhances cartilage destruction in a mouse osteoarthritis model.

Zhang X, Zhu J, Liu F, Li Y, Chandra A, Levin LS, Beier F, Enomoto-Iwamoto M, Qin L - Bone Res (2014)

Bottom Line: To study its function in OA progression, we performed surgical destabilization of the medial meniscus (DMM) to induce OA in two mouse models with reduced EGFR activity, one with genetic modification (Egfr(Wa5/+) mice) and the other one with pharmacological inhibition (gefitinib treatment).Histological analyses and scoring at 3 months post-surgery revealed increased cartilage destruction and accelerated OA progression in both mouse models.Immunohistochemistry showed increased aggrecan degradation in these mouse models, which coincides with elevated amounts of ADAMTS5 and matrix metalloproteinase 13 (MMP13), the principle proteinases responsible for aggrecan degradation, in the articular cartilage after DMM surgery.

View Article: PubMed Central - PubMed

Affiliation: Department of Orthopaedic Surgery, School of Medicine, University of Pennsylvania , Philadelphia, PA, USA ; Department of Physiology, School of Basic Medical Sciences, Wuhan University , Wuhan, China.

ABSTRACT
Osteoarthritis (OA) is a degenerative joint disease and a major cause of pain and disability in older adults. We have previously identified epidermal growth factor receptor (EGFR) signaling as an important regulator of cartilage matrix degradation during epiphyseal cartilage development. To study its function in OA progression, we performed surgical destabilization of the medial meniscus (DMM) to induce OA in two mouse models with reduced EGFR activity, one with genetic modification (Egfr(Wa5/+) mice) and the other one with pharmacological inhibition (gefitinib treatment). Histological analyses and scoring at 3 months post-surgery revealed increased cartilage destruction and accelerated OA progression in both mouse models. TUNEL staining demonstrated that EGFR signaling protects chondrocytes from OA-induced apoptosis, which was further confirmed in primary chondrocyte culture. Immunohistochemistry showed increased aggrecan degradation in these mouse models, which coincides with elevated amounts of ADAMTS5 and matrix metalloproteinase 13 (MMP13), the principle proteinases responsible for aggrecan degradation, in the articular cartilage after DMM surgery. Furthermore, hypoxia-inducible factor 2α (HIF2α), a critical catabolic transcription factor stimulating MMP13 expression during OA, was also upregulated in mice with reduced EGFR signaling. Taken together, our findings demonstrate a primarily protective role of EGFR during OA progression by regulating chondrocyte survival and cartilage degradation.

No MeSH data available.


Related in: MedlinePlus

Mice with reduced EGFR activity have more hypertrophicchondrocytes in the articular cartilage. RepresentativeSafranin O/Fast Green staining images of sham-operatedtibial plateau fromEgfrWa5/+ mice(a) and gefitinib-treated mice(b) and their respectivecontrols.
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fig3: Mice with reduced EGFR activity have more hypertrophicchondrocytes in the articular cartilage. RepresentativeSafranin O/Fast Green staining images of sham-operatedtibial plateau fromEgfrWa5/+ mice(a) and gefitinib-treated mice(b) and their respectivecontrols.

Mentions: Chondrocyte hypertrophy is routinely seen in the developmentof osteoarthritis. Since our previous work demonstratedthat EGFR deficiency induces expansion of thehypertrophic zone of the growth plate in young rats andneonatal mice,3 we quantified the number ofhypertrophic chondrocytes in the articular cartilageand normalized it against the total cartilage area. Inthe sham-operated contralateral joints, we observed asignificant 111% increase of hypertrophicchondrocytes inEgfrWa5/+ mice(WT: 0.12±0.03 cells per mm2;EgfrWa5/+:0.25±0.02 cells per mm2,n=5 in each group,P=0.01, Figure 3a) and a similar trend ofincrease in gefitinib-treated mice (vehicle-treated:0.19±0.02 cells per mm2;gefitinib-treated: 0.24±0.03 cells permm2, n=5 in eachgroup, P=0.17, Figure 3b) comparedto their respective controls. We found that it wasdifficult to perform similar measurement at the DMMknees because of severe erosion and/or loss ofarticular cartilage in the EGFR deficient group. Thesefindings indicate that EGFR prevents chondrocytehypertrophy and may explain why mice with reduced EGFRsignaling are predisposed to the development ofosteoarthritis.


Reduced EGFR signaling enhances cartilage destruction in a mouse osteoarthritis model.

Zhang X, Zhu J, Liu F, Li Y, Chandra A, Levin LS, Beier F, Enomoto-Iwamoto M, Qin L - Bone Res (2014)

Mice with reduced EGFR activity have more hypertrophicchondrocytes in the articular cartilage. RepresentativeSafranin O/Fast Green staining images of sham-operatedtibial plateau fromEgfrWa5/+ mice(a) and gefitinib-treated mice(b) and their respectivecontrols.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4472123&req=5

fig3: Mice with reduced EGFR activity have more hypertrophicchondrocytes in the articular cartilage. RepresentativeSafranin O/Fast Green staining images of sham-operatedtibial plateau fromEgfrWa5/+ mice(a) and gefitinib-treated mice(b) and their respectivecontrols.
Mentions: Chondrocyte hypertrophy is routinely seen in the developmentof osteoarthritis. Since our previous work demonstratedthat EGFR deficiency induces expansion of thehypertrophic zone of the growth plate in young rats andneonatal mice,3 we quantified the number ofhypertrophic chondrocytes in the articular cartilageand normalized it against the total cartilage area. Inthe sham-operated contralateral joints, we observed asignificant 111% increase of hypertrophicchondrocytes inEgfrWa5/+ mice(WT: 0.12±0.03 cells per mm2;EgfrWa5/+:0.25±0.02 cells per mm2,n=5 in each group,P=0.01, Figure 3a) and a similar trend ofincrease in gefitinib-treated mice (vehicle-treated:0.19±0.02 cells per mm2;gefitinib-treated: 0.24±0.03 cells permm2, n=5 in eachgroup, P=0.17, Figure 3b) comparedto their respective controls. We found that it wasdifficult to perform similar measurement at the DMMknees because of severe erosion and/or loss ofarticular cartilage in the EGFR deficient group. Thesefindings indicate that EGFR prevents chondrocytehypertrophy and may explain why mice with reduced EGFRsignaling are predisposed to the development ofosteoarthritis.

Bottom Line: To study its function in OA progression, we performed surgical destabilization of the medial meniscus (DMM) to induce OA in two mouse models with reduced EGFR activity, one with genetic modification (Egfr(Wa5/+) mice) and the other one with pharmacological inhibition (gefitinib treatment).Histological analyses and scoring at 3 months post-surgery revealed increased cartilage destruction and accelerated OA progression in both mouse models.Immunohistochemistry showed increased aggrecan degradation in these mouse models, which coincides with elevated amounts of ADAMTS5 and matrix metalloproteinase 13 (MMP13), the principle proteinases responsible for aggrecan degradation, in the articular cartilage after DMM surgery.

View Article: PubMed Central - PubMed

Affiliation: Department of Orthopaedic Surgery, School of Medicine, University of Pennsylvania , Philadelphia, PA, USA ; Department of Physiology, School of Basic Medical Sciences, Wuhan University , Wuhan, China.

ABSTRACT
Osteoarthritis (OA) is a degenerative joint disease and a major cause of pain and disability in older adults. We have previously identified epidermal growth factor receptor (EGFR) signaling as an important regulator of cartilage matrix degradation during epiphyseal cartilage development. To study its function in OA progression, we performed surgical destabilization of the medial meniscus (DMM) to induce OA in two mouse models with reduced EGFR activity, one with genetic modification (Egfr(Wa5/+) mice) and the other one with pharmacological inhibition (gefitinib treatment). Histological analyses and scoring at 3 months post-surgery revealed increased cartilage destruction and accelerated OA progression in both mouse models. TUNEL staining demonstrated that EGFR signaling protects chondrocytes from OA-induced apoptosis, which was further confirmed in primary chondrocyte culture. Immunohistochemistry showed increased aggrecan degradation in these mouse models, which coincides with elevated amounts of ADAMTS5 and matrix metalloproteinase 13 (MMP13), the principle proteinases responsible for aggrecan degradation, in the articular cartilage after DMM surgery. Furthermore, hypoxia-inducible factor 2α (HIF2α), a critical catabolic transcription factor stimulating MMP13 expression during OA, was also upregulated in mice with reduced EGFR signaling. Taken together, our findings demonstrate a primarily protective role of EGFR during OA progression by regulating chondrocyte survival and cartilage degradation.

No MeSH data available.


Related in: MedlinePlus