4.6 Article

Intraarticular injection of SHP2 inhibitor SHP099 promotes the repair of rabbit full-thickness cartilage defect

期刊

JOURNAL OF ORTHOPAEDIC TRANSLATION
卷 32, 期 -, 页码 112-120

出版社

ELSEVIER
DOI: 10.1016/j.jot.2022.01.001

关键词

Src-homology 2-containing protein tyrosine phosphatase 2; Cartilage repair; Synovial mesenchymal stem cells

资金

  1. National Science Foundation of China (NSFC) [81802196, 81572129]
  2. Key Program of NSFC [81730067]
  3. Special Program of Chinese Academy of Science [XDA16020805]
  4. Jiangsu Provincial Key Medical Center Foundation
  5. Jiangsu Provincial Medical Outstanding Talent Foundation
  6. Jiangsu Provincial Key Medical Talent Foundation
  7. National Science Foundation of China [81772335]

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This study demonstrates that the SHP2 inhibitor SHP099 promotes chondrogenesis and the repair of cartilage defects, suggesting its potential as a therapeutic drug for cartilage repair.
Background: Cartilage repair has been a challenge in the field of orthopaedics for decades, highlighting the significance of investigating potential therapeutic drugs. In this study, we explored the effect of the SHP2 inhibitor SHP099, a small-molecule drug, on cartilage repair. Methods: Human synovial mesenchymal stem cells (SMSCs) were isolated, and their three-way differentiation potential was examined. After treatment with chondrogenic medium, the chondrogenic effect of SHP099 on SMSCs was examined by western blot, qPCR, and immunofluorescence (IF). Micro-mass culture was also used to detect the effect of SHP099. To explore the chondrogenic effects of SHP099 in vivo, full-thickness cartilage defects with microfractures were constructed in the right femoral trochlea of New Zealand White rabbits. Intraarticular injection of SHP099 or normal saline was performed twice a week for 6 weeks. Cartilage repair was evaluated by haematoxylin and eosin (HE) staining and safranin O/fast green staining. Immunohistochemistry (IHC) for collagen II (COL2) was also conducted to verify the abundance of cartilage extracellular matrix after SHP099 treatment. The mechanism involving yes-associated protein (YAP) and WNT signalling was investigated in vitro. Results: SMSCs isolated from human synovium have optimal multi-differentiation potential. SHP099 increased chondrogenic marker (SOX9, COL2) expression and decreased hypertrophic marker (COL10, RUNX2) expression in SMSCs. In micro-mass culture, the SHP099-induced cartilage tissues had a better result of Safranin O and Toluidine blue staining and are enriched in cartilage-specific collagen II. Inhibition of YAP and WNT signalling was also observed. Moreover, compared to the normal saline group at 6 weeks, intraarticular injection of SHP099 resulted in better defect filling, forming increased hyaline cartilage-like tissue with higher levels of glycosaminoglycan (GAG) and COL2. Conclusion: SHP099 promotes the repair of rabbit full-thickness cartilage defects, representing a potential therapeutic drug for cartilage repair. The Translational potential of this article: This study provides evidence that SHP2 inhibition promotes chondrogenesis and the repair of cartilage in defect area, which could be a novel therapeutic approach for cartilage repair.

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