Epidermal Growth Factor Receptor (EGFR) Signaling Regulates Epiphyseal Cartilage Development through β-Catenin-dependent and -independent Pathways

Zhang, Xianrong; Zhu, Jing; Li, Yumei; Lin, Tiantian; Siclari, Valerie A.; Chandra, Abhishek; Candela, Elena M.; Koyama, Eiki; Enomoto‐Iwamoto, Motomi; Qin, Ling

doi:10.1074/jbc.m113.463554

Cited by 53 publications

(64 citation statements)

References 51 publications

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“…To our knowledge, this is the first study unambiguously demonstrating the important roles of EGFR signaling in maintaining articular cartilage homeostasis. Our results illustrate that EGFR mainly promotes anabolic activity in articular cartilage, which is opposite from its catabolic activity during growth plate development and SOC formation discovered in our previous reports (14,15). Because articular chondrocytes arise from a distinct progenitor population from growth plate and epiphyseal chondrocytes (29), the EGFR function we identified in endochondral ossification may not be the same in articular cartilage.…”

Section: Discussioncontrasting

confidence: 44%

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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.

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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

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Section: Discussioncontrasting

confidence: 44%

“…In the past, we established a chondrocyte-specific Egfr knockout mouse model to demonstrate a pivotal role of EGFR signaling in growth plate development and secondary ossification center (SOC) formation (14,15). In this study, we used this model to investigate the function of EGFR in articular cartilage development.…”

Section: Significancementioning

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.

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“…This is similar to the phenotype observed following loss of Egfr signaling in the growth plate (Zhang et al, 2011). In addition to activating the ERK and p38 pathways (outlined in Zhang et al, 2013), growth factors such as EGF are known to stimulate the generation of hydrogen peroxide via activation of the NADPH oxidase Nox1, by a mechanism involving PI3K and Rac1 (Bae et al, 1997;Fan et al, 2005). Notably, Morita et al found that reactive oxygen species (ROS) are specifically generated in the hypertrophic zone of the growth plate (Morita et al, 2007).…”

Section: Igf1 Signaling Controls the Last Phase Of Growth During Chonmentioning

confidence: 49%

“…Qin and colleagues have noted that, although upregulation of Mmp9 and RANKL by Egfr signaling is partially mediated by the canonical Wnt/β-catenin pathway, Egfr-induced expression of Mmp13 is mediated via a distinct pathway (Zhang et al, 2013). Conditional knockout of both Erk1 and Erk2 in the mesenchymal precursors of the appendicular skeleton resulted in a remarkable expansion of the Col10a1 expression domain within the growth plate, coupled with a lack of expression of late hypertrophic markers such as VEGFA and RANKL in this tissue (Matsushita et al, 2009).…”

Section: Igf1 Signaling Controls the Last Phase Of Growth During Chonmentioning

confidence: 99%

“…In micromass cultures, BMP signaling initially regulates the compaction of mesenchymal cells that is required to acquire a cohesive cell behavior (Barna and Niswander, 2007) (Liu et al, 2002;Hung et al, 2007), PTHrP (St-Jacques et al, 1999), CNP (Chusho et al, 2001), EGF/TGFα (Ren et al, 1997), Ihh , VEGFA (Zelzer et al, 2001) and RANKL (Zhang et al, 2011). Receptors: Fgfr1 (Jacob et al, 2006), Fgfr2 (Yu et al, 2003), Fgfr3 (de Frutos et al, 2007, Pth1r de Frutos et al, 2007), Npr2 (Yamashita et al, 2000), Npr3 (Yamashita et al, 2000) and Egfr (Zhang et al, 2013). Transcription factors: Sox5/6/9 , Runx2 (Inada et al, 1999;Kim et al, 1999), Mef2c and Mef2d (Mef2c/d) (Arnold et al, 2007), Foxa2 (Ionescu et al, 2012), and Zfp521 (Correa et al, 2010).…”

Section: Tgfβ Signaling In Chondrogenesismentioning

confidence: 99%

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A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation

2015

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Decades of work have identified the signaling pathways that regulate the differentiation of chondrocytes during bone formation, from their initial induction from mesenchymal progenitor cells to their terminal maturation into hypertrophic chondrocytes. Here, we review how multiple signaling molecules, mechanical signals and morphological cell features are integrated to activate a set of key transcription factors that determine and regulate the genetic program that induces chondrogenesis and chondrocyte differentiation. Moreover, we describe recent findings regarding the roles of several signaling pathways in modulating the proliferation and maturation of chondrocytes in the growth plate, which is the 'engine' of bone elongation.

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Disturbed Cartilage and Joint Homeostasis Resulting From a Loss of Mitogen‐Inducible Gene 6 in a Mouse Model of Joint Dysfunction

Pest

Russell

Zhang

et al. 2014

Arthritis & Rheumatology

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Objective Mitogen-inducible gene 6 (MIG-6) regulates epidermal growth factor receptor (EGFR) signaling in synovial joint tissues. Whole-body knockout of the Mig6 gene in mice has been shown to induce osteoarthritis and joint degeneration. To evaluate the role of chondrocytes in this process, Mig6 was conditionally deleted from Col2a1-expressing cell types in the cartilage of mice. Methods Bone and cartilage in the synovial joints of cartilage-specific Mig6-deleted (knockout [KO]) mice and control littermates were compared. Histologic staining and immunohistochemical analyses were used to evaluate joint pathology as well as the expression of key extracellular matrix and regulatory proteins. Calcified tissue in synovial joints was assessed by micro–computed tomography (micro-CT) and whole-skeleton staining. Results Formation of long bones was found to be normal in KO animals. Cartilage thickness and proteoglycan staining of articular cartilage in the knee joints of 12-week-old KO mice were increased as compared to controls, with higher cellularity throughout the tissue. Radiopaque chondro-osseous nodules appeared in the knees of KO animals by 12 weeks of age and progressed to calcified bone–like tissue by 36 weeks of age. Nodules were also observed in the spine of 36-week-old animals. Erosion of bone at ligament entheses was evident by 12 weeks of age, by both histologic and micro-CT assessment. Conclusion MIG-6 expression in chondrocytes is important for the maintenance of cartilage and joint homeostasis. Dysregulation of EGFR signaling in chondrocytes results in anabolic activity in cartilage, but erosion of ligament entheses and the formation of ectopic chondro-osseous nodules severely disturb joint physiology.

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Epidermal Growth Factor Receptor (EGFR) Signaling Regulates Epiphyseal Cartilage Development through β-Catenin-dependent and -independent Pathways

Cited by 53 publications

References 51 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

A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation

Disturbed Cartilage and Joint Homeostasis Resulting From a Loss of Mitogen‐Inducible Gene 6 in a Mouse Model of Joint Dysfunction

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