title: EGFR signaling is critical for maintaining the superficial layer of articular cartilage and preventing osteoarthritis initiation.
abstract: 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.
authors.affiliation: Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.|Department of Orthopaedic Surgery, School of Medicine, ShiHeZi University, ShiHeZi, Xinjiang 832003, China.
authors.forename: Haoruo
authors.initials: H
authors.lastname: Jia
authors.affiliation: Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.|Department of Orthopaedics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.|Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Tong
authors.affiliation: School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA 19104.
authors.forename: Basak
authors.initials: B
authors.lastname: Doyran
authors.affiliation: School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Zeyang
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.|Department of Orthopaedics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Luqiang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.|Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Xianrong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Mechanical Engineering, University of Delaware, Newark, DE 19716.
authors.forename: Yilu
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Physics and Center for Biomedical Research, Oakland University, Rochester, MI 48309.
authors.forename: Farid
authors.initials: F
authors.lastname: Badar
authors.affiliation: Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Chandra
authors.affiliation: Department of Mechanical Engineering, University of Delaware, Newark, DE 19716.
authors.forename: X Lucas
authors.initials: XL
authors.lastname: Lu
authors.affiliation: Department of Physics and Center for Biomedical Research, Oakland University, Rochester, MI 48309.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xia
authors.affiliation: School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA 19104.
authors.forename: Lin
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.|Department of Surgery, The Children's Hospital of Philadelphia, Pennsylvania, PA 19104.
authors.forename: Motomi
authors.initials: M
authors.lastname: Enomoto-Iwamoto
authors.affiliation: Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; qinling@mail.med.upenn.edu.
authors.forename: Ling
authors.initials: L
authors.lastname: Qin
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D002358:Cartilage, Articular / Q000378:metabolism*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D020219:Chondrogenesis; D066246:ErbB Receptors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010003:Osteoarthritis / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D011509:Proteoglycans / Q000378:metabolism; D015398:Signal Transduction; D000099158:Proteoglycan 4
chemical_list: D066246:ErbB Receptors; D011509:Proteoglycans; C498837:Prg4 protein, mouse; D000099158:Proteoglycan 4; C541485:EGFR protein, mouse
keywords: EGFR; articular cartilage; chondrocyte; lubrication; osteoarthritis