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We previously demonstrated that epidermal growth factor receptor (EGFR) signaling is essential for maintaining chondroprogenitors during articular cartilage development and homeostasis. Here, we used a nonsurgical, loading-induced PTOA mouse model to investigate the protective action of EGFR signaling. A single bout of cyclic tibial loading at a peak force of 6\u00a0N injured cartilage at the posterior aspect of lateral femoral condyle. Similar loading at a peak force of 9\u2009N ruptured the anterior cruciate ligament, causing additional cartilage damage at the medial compartment and ectopic cartilage formation in meniscus and synovium. Constitutively overexpression of an EGFR ligand, heparin binding EGF-like growth factor (HBEGF), in chondrocytes significantly reduced cartilage injury length, synovitis, and pain after 6\u00a0N loading and mitigated medial side cartilage damage and ectopic cartilage formation after 9\u00a0N loading. Mechanistically, overactivation of EGFR signaling protected chondrocytes from loading-induced apoptosis and loss of proliferative ability and lubricant synthesis. Overexpressing HBEGF in adult cartilage starting right before 6\u00a0N loading had similar beneficial effects. In contrast, inactivating EGFR in adult cartilage led to accelerated PTOA progression with elevated cartilage Mankin score and synovitis score and increased ectopic cartilage formation. As a therapeutic approach, we constructed a nanoparticle conjugated with the EGFR ligand TGF\u03b1. Intra-articular injections of this nanoconstruct once every 3\u2009weeks for 12\u2009weeks partially mitigated PTOA symptoms in cartilage and synovium after 6\u00a0N loading. Our findings demonstrate the anabolic actions of EGFR signaling in maintaining articular cartilage during PTOA development and shed light on developing a novel nanomedicine for PTOA. \u00a9 2022 American Society for Bone and Mineral Research (ASBMR).<\/jats:p>","DOI":"10.1002\/jbmr.4717","type":"journal-article","created":{"date-parts":[[2022,9,30]],"date-time":"2022-09-30T09:07:26Z","timestamp":1664528846000},"page":"2498-2511","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Activating EGFR Signaling Attenuates Osteoarthritis Development Following Loading Injury in Mice"],"prefix":"10.1093","volume":"37","author":[{"given":"Tao","family":"Gui","sequence":"first","affiliation":[{"name":"Center for Joint Surgery and Sports Medicine, the First Affiliated Hospital Jinan University Guangzhou China"},{"name":"Department of Orthopaedic Surgery, Perelman School of Medicine University of Pennsylvania Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulong","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China"},{"name":"Department of Orthopaedic Surgery, Perelman School of Medicine University of Pennsylvania Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijun","family":"Luo","sequence":"additional","affiliation":[{"name":"School of Agricultural Engineering Jiangsu University Zhenjiang China"},{"name":"Department of Bioengineering University of Pennsylvania Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Perelman School of Medicine University of Pennsylvania Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leilei","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Perelman School of Medicine University of Pennsylvania Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lutian","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Perelman School of Medicine University of Pennsylvania Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Beier","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry University of Western Ontario London ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles L.","family":"Nelson","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Perelman School of Medicine University of Pennsylvania Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7758-1753","authenticated-orcid":false,"given":"Andrew","family":"Tsourkas","sequence":"additional","affiliation":[{"name":"Department of Bioengineering University of Pennsylvania Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X. Sherry","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Perelman School of Medicine University of Pennsylvania Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9589-9607","authenticated-orcid":false,"given":"Motomi","family":"Enomoto-Iwamoto","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, School of Medicine University of Maryland Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feifan","family":"Yu","sequence":"additional","affiliation":[{"name":"AlphaThera LLC Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiliang","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Bioengineering University of Pennsylvania Philadelphia PA 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