Effects And Mechanism Of Gefitinib On Intervertebral Disc Degeneration And Meniscal Injury

Part I:Therapeutic effects of gefitinib-encapsulated thermosensitive injectable hydrogel in intervertebral disc degenerationIntervertebral disc(IVD)degeneration is one of the most widespread musculoskeletal diseases worldwide,which remains an intractable clinical challenge.The purpose of our study is to investigate the therapeutic potential of the small molecule gefitinib(an epidermal growth factor receptor(EGFR)inhibitor)in ameliorating IVD degeneration.Aberrant EGFR activation levels in both human and rat degenerative IVD prompted us to investigate the functional roles of EGFR by utilizing inducible cartilage-specific EGFR-deficient mice.We demonstrated that conditional EGFR deletion in mice increased nucleus pulposus(NP)extracellular matrix(ECM)production,and decreased MMP 13 expression and autophagy marker activation.These outcomes are comparable to the use of a controlled-release injectable thermosensitive hydrogel of small molecule EGFR inhibitor,gefitinib,to block EGFR activity in a puncture-induced rat model.We also conducted a retrospective study involving patients with non-small cell lung cancer and IVD degeneration who received gefitinib treatment from 2010 to 2015.Gefitinib-treated patients displayed a more slowly progressing and deforming "pathologic" disc degeneration,in contrast,to control subjects.These findings provide conclusive evidence that suppression of EGFR by the FDA-approved drug gefitinib can re-activate NPs autophagy and restore IVD homeostasis;thus,demonstrating the unique advantages of gefitinib as a small molecule drug for treating IVD degeneration.Part ?:Delivery of epidermal growth factor receptor inhibitor via a customized collagen scaffold promotes meniscal defect regeneration in a rabbit modelMeniscal injury is one of the most common knee joint injuries,which remains an intractable challenge in clinical practice to date.Aberrant epidermal growth factor receptor(EGFR)activation levels in both human and mice menisci following injury,prompted us to investigate the functional role of EGFR by utilizing an inducible cartilage-specific EGFR-deficient mouse model.We demonstrated that conditional EGFR deletion in mice resulted in increased partial meniscectomy-induced ECM production within the meniscus,which is comparable to utilization of the small molecule EGFR inhibitor,gefitinib,to block EGFR activity.Here,we combined intra-articular delivery of gefitinib with an implanted customized collagen scaffold to substitute for lost meniscal tissue,as well as to promote meniscal regeneration and prevent osteoarthritis(OA)progression in a rabbit meniscectomy model.