PMID- 35865095 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220723 IS - 2211-3835 (Print) IS - 2211-3843 (Electronic) IS - 2211-3835 (Linking) VI - 12 IP - 7 DP - 2022 Jul TI - Targeting macrophagic SHP2 for ameliorating osteoarthritis via TLR signaling. PG - 3073-3084 LID - 10.1016/j.apsb.2022.02.010 [doi] AB - Osteoarthritis (OA), in which M1 macrophage polarization in the synovium exacerbates disease progression, is a major cause of cartilage degeneration and functional disabilities. Therapeutic strategies of OA designed to interfere with the polarization of macrophages have rarely been reported. Here, we report that SHP099, as an allosteric inhibitor of src-homology 2-containing protein tyrosine phosphatase 2 (SHP2), attenuated osteoarthritis progression by inhibiting M1 macrophage polarization. We demonstrated that M1 macrophage polarization was accompanied by the overexpression of SHP2 in the synovial tissues of OA patients and OA model mice. Compared to wild-type (WT) mice, myeloid lineage conditional Shp2 knockout (cKO) mice showed decreased M1 macrophage polarization and attenuated severity of synovitis, an elevated expression of cartilage phenotype protein collagen II (COL2), and a decreased expression of cartilage degradation markers collagen X (COL10) and matrix metalloproteinase 3 (MMP3) in OA cartilage. Further mechanistic analysis showed thatSHP099 inhibited lipopolysaccharide (LPS)-induced Toll-like receptor (TLR) signaling mediated by nuclear factor kappa B (NF-kappaB) and PI3K-AKT signaling. Moreover, intra-articular injection of SHP099 also significantly attenuated OA progression, including joint synovitis and cartilage damage. These results indicated that allosteric inhibition of SHP2 might be a promising therapeutic strategy for the treatment of OA. CI - (c) 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. FAU - Sun, Ziying AU - Sun Z AD - State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China. AD - Laboratory for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing 210093, China. FAU - Liu, Qianqian AU - Liu Q AD - State Key Laboratory of Pharmaceutical Biotechnology, Department of Biotechnology and Pharmaceutical Sciences, School of Life Science, Nanjing University, Nanjing 210023, China. FAU - Lv, Zhongyang AU - Lv Z AD - State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China. AD - Laboratory for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing 210093, China. FAU - Li, Jiawei AU - Li J AD - State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China. AD - Laboratory for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing 210093, China. FAU - Xu, Xingquan AU - Xu X AD - State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China. AD - Laboratory for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing 210093, China. FAU - Sun, Heng AU - Sun H AD - State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China. AD - Laboratory for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing 210093, China. FAU - Wang, Maochun AU - Wang M AD - State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China. AD - Laboratory for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing 210093, China. FAU - Sun, Kuoyang AU - Sun K AD - State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China. AD - Laboratory for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing 210093, China. FAU - Shi, Tianshu AU - Shi T AD - State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China. AD - Laboratory for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing 210093, China. FAU - Liu, Zizheng AU - Liu Z AD - State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China. AD - Laboratory for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing 210093, China. FAU - Tan, Guihua AU - Tan G AD - State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China. AD - Laboratory for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing 210093, China. FAU - Yan, Wenqiang AU - Yan W AD - State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China. AD - Laboratory for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing 210093, China. FAU - Wu, Rui AU - Wu R AD - State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China. AD - Laboratory for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing 210093, China. FAU - Yang, Yannick Xiaofan AU - Yang YX AD - State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China. AD - Drum Tower of Clinical Medicine, Nanjing Medical University, Nanjing 210008, China. FAU - Ikegawa, Shiro AU - Ikegawa S AD - State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China. AD - Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Science (IMS, RIKEN), Tokyo 108-8639, Japan. FAU - Jiang, Qing AU - Jiang Q AD - State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China. AD - Laboratory for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing 210093, China. FAU - Sun, Yang AU - Sun Y AD - State Key Laboratory of Pharmaceutical Biotechnology, Department of Biotechnology and Pharmaceutical Sciences, School of Life Science, Nanjing University, Nanjing 210023, China. FAU - Shi, Dongquan AU - Shi D AD - State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China. AD - Laboratory for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing 210093, China. LA - eng PT - Journal Article DEP - 20220217 PL - Netherlands TA - Acta Pharm Sin B JT - Acta pharmaceutica Sinica. B JID - 101600560 PMC - PMC9293663 OTO - NOTNLM OT - Cartilage degradation OT - M1 macrophage polarization OT - Macrophage OT - Osteoarthritis OT - SHP099 OT - SHP2 OT - Synovitis OT - Toll-like receptor signaling EDAT- 2022/07/23 06:00 MHDA- 2022/07/23 06:01 PMCR- 2022/02/17 CRDT- 2022/07/22 02:20 PHST- 2021/10/17 00:00 [received] PHST- 2021/12/15 00:00 [revised] PHST- 2022/01/20 00:00 [accepted] PHST- 2022/07/22 02:20 [entrez] PHST- 2022/07/23 06:00 [pubmed] PHST- 2022/07/23 06:01 [medline] PHST- 2022/02/17 00:00 [pmc-release] AID - S2211-3835(22)00060-0 [pii] AID - 10.1016/j.apsb.2022.02.010 [doi] PST - ppublish SO - Acta Pharm Sin B. 2022 Jul;12(7):3073-3084. doi: 10.1016/j.apsb.2022.02.010. Epub 2022 Feb 17.