Cartilage-specific deletion of Mig-6 results in osteoarthritis-like disorder with excessive articular chondrocyte proliferation

Staal, Ben; Williams, Bart O.; Beier, Frank; Woude, George F. Vande; Zhang, Yu Wen

doi:10.1073/pnas.1400744111

Cited by 52 publications

(57 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies of EGFR signaling in articular cartilage development and degeneration focused on an indirect approach analyzing mice lacking Mig-6, an EGFR inhibitor (9)(10)(11)(12). Because Mig-6 is not specific to EGFR, those results are too complicated to clearly interpret EGFR function.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

EGFR signaling is critical for maintaining the superficial layer of articular cartilage and preventing osteoarthritis initiation

Jia

Tong

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Osteoarthritis (OA) is the most common joint disease, characterized by progressive destruction of the articular cartilage. The surface of joint cartilage is the first defensive and affected site of OA, but our knowledge of genesis and homeostasis of this superficial zone is scarce. EGFR signaling is important for tissue homeostasis. Immunostaining revealed that its activity is mostly dominant in the superficial layer of healthy cartilage but greatly diminished when OA initiates. To evaluate the role of EGFR signaling in the articular cartilage, we studied a cartilage-specific Egfr-deficient (CKO) mouse model (Col2-Cre EgfrWa5/flox). These mice developed early cartilage degeneration at 6 mo of age. By 2 mo of age, although their gross cartilage morphology appears normal, CKO mice had a drastically reduced number of superficial chondrocytes and decreased lubricant secretion at the surface. Using superficial chondrocyte and cartilage explant cultures, we demonstrated that EGFR signaling is critical for maintaining the number and properties of superficial chondrocytes, promoting chondrogenic proteoglycan 4 (Prg4) expression, and stimulating the lubrication function of the cartilage surface. In addition, EGFR deficiency greatly disorganized collagen fibrils in articular cartilage and strikingly reduced cartilage surface modulus. After surgical induction of OA at 3 mo of age, CKO mice quickly developed the most severe OA phenotype, including a complete loss of cartilage, extremely high surface modulus, subchondral bone plate thickening, and elevated joint pain. Taken together, our studies establish EGFR signaling as an important regulator of the superficial layer during articular cartilage development and OA initiation.EGFR | articular cartilage | chondrocyte | lubrication | osteoarthritis

show abstract

Section: Discussionmentioning

confidence: 99%

“…Mig-6 null mice develop a severe OA-like joint degeneration phenotype at an early adult stage (9). However, mice with limb-(Prx1-Cre) or cartilage-(Col2-Cre) specific deletion of Mig-6 showed a much milder OA phenotype (10)(11)(12). Indeed, a…”

mentioning

confidence: 99%

EGFR signaling is critical for maintaining the superficial layer of articular cartilage and preventing osteoarthritis initiation

Jia

Tong

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…In the developmental context, EGFR activity stimulates increased cartilage thickness and chondrocyte proliferation (38). Indeed, we have reported increased chondrocyte proliferation in articular cartilage treated with exogenous TGFa (9), and cartilage-specific knockout of Mig-6 also leads to excessive articular chondrocyte proliferation (39,40). Thus, moderate suppression of EGFR activity likely abolishes protective anabolic effects in early OA development (e.g., in the DMM OA model), whereas excessive EGFR activity in later OA stages (represented in our more aggressive rat posttraumatic OA model) is deleterious.…”

Section: Discussionmentioning

confidence: 99%

Reduction in Disease Progression by Inhibition of Transforming Growth Factor α–CCL2 Signaling in Experimental Posttraumatic Osteoarthritis

Appleton

Usmani

Pest

et al. 2015

Arthritis & Rheumatology

Self Cite

View full text Add to dashboard Cite

Objective. Transforming growth factor a (TGFa) is increased in osteoarthritic (OA) cartilage in rats and humans and modifies chondrocyte phenotype. CCL2 is increased in OA cartilage and stimulates proteoglycan loss. This study was undertaken to test whether TGFa and CCL2 cooperate to promote cartilage degradation and whether inhibiting either reduces disease progression in a rat model of posttraumatic OA.Methods. Microarray analysis was used to profile expression of messenger RNA (mRNA) for Tgfa, Ccl2, and related genes in a rat model of posttraumatic OA. Rat primary chondrocytes and articular cartilage explants were treated with TGFa in the presence or absence of MEK-1/ 2, p38, phosphatidylinositol 3-kinase, Rho-associated protein kinase, or CCR2 inhibitors and immunostained for markers of cartilage degradation. The rat model was used to administer pharmacologic inhibitors of TGFa (AG1478) and CCL2 (RS504393) signaling for up to 10 weeks and assess histopathology and serum biomarkers of cartilage synthesis (C-propeptide of type II collagen [CPII]) and breakdown (C2C).Results. Tgfa and Ccl2 mRNA were simultaneously up-regulated in articular cartilage in the rat model of posttraumatic OA. TGFa induced expression of CCL2, Mmp3, and Tnf in primary chondrocytes. Cleavage of type II collagen and aggrecan (by matrix metalloproteinases and ADAMTS-4/5, respectively) induced by TGFa was blocked by pharmacologic inhibition of CCL2 in cartilage explants. In vivo pharmacologic inhibition of TGFa or CCL2 signaling reduced Osteoarthritis Research Society International cartilage histopathology scores and increased serum CPII levels, but only TGFa inhibition reduced C2C levels intreated versus untreated rat OA cartilage.Conclusion. TGFa signaling stimulates cartilage degradation via a CCL2-dependent mechanism, but pharmacologic inhibition of the TGFa-CCL2 axis reduces experimental posttraumatic OA progression in vivo.Osteoarthritis (OA) is a degenerative synovial joint condition that affects 10% of North Americans (1,2). Posttraumatic OA results from premature onset of OA after joint injury (e.g., anterior cruciate ligament tear). Approximately 12% of OA diagnoses are due to posttraumatic OA (3), although this is likely an underestimate due to incomplete patient recall. In recent years, potential OA therapies have moved toward clinical evaluation (e.g., phase I clinical trials are under way with intraarticular recombinant bone morphogenetic protein 7 (4) and fibroblast growth factor 18 [ClinicalTrials.gov identifier: NCT01033994]). Unfortunately, most of the therapies have either been ineffective (e.g., phase II clinical trials with the inducible nitric oxide synthase

show abstract

“…It has been recognized for a long time that EGF is a potent mitogen for cultured chondrocytes (36,37). Interestingly, recent studies with either limb or cartilage targeted deletion of the intracellular EGFR inhibitor Mig-6 revealed remarkably thickened articular cartilage in those mice at early adult stage due to enhanced chondrocyte proliferation (12,13). Although we did not notice a reduction in cartilage thickness in the sham-operated knees in mice with reduced EGFR activity, a close examination did reveal an increase in the number of hypertrophic chondrocytes, suggesting that EGFR prevents chondrocyte hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

Reduced EGFR signaling enhances cartilage destruction in a mouse osteoarthritis model

et al. 2014

Self Cite

View full text Add to dashboard Cite

Osteoarthritis (OA) is a degenerative joint disease and a major cause of pain and disability in older adults. We have previously identified 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 (EgfrWa5/+ 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 up-regulated 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.

show abstract

Cartilage-specific deletion of Mig-6 results in osteoarthritis-like disorder with excessive articular chondrocyte proliferation

Cited by 52 publications

References 35 publications

EGFR signaling is critical for maintaining the superficial layer of articular cartilage and preventing osteoarthritis initiation

EGFR signaling is critical for maintaining the superficial layer of articular cartilage and preventing osteoarthritis initiation

Reduction in Disease Progression by Inhibition of Transforming Growth Factor α–CCL2 Signaling in Experimental Posttraumatic Osteoarthritis

Reduced EGFR signaling enhances cartilage destruction in a mouse osteoarthritis model

Contact Info

Product

Resources

About