Therapeutic effect of the injectable thermosensitive hydrogel loaded with SHP099 on intervertebral disc degeneration

• Published in: Life sciences (1973) 2021-02, Vol.266, p.118891-118891, Article 118891
• Main Authors: Wang, Jingcheng, Huang, Leizhen, Huang, Yong, Jiang, Yulin, Zhang, Li, Feng, Ganjun, Liu, Limin
• Format: Article
• Language: English
• Subjects: Aggrecan; Animals; Collagen (type II); Degeneration; Female; Homology; Hydrogels; Hydrogels - administration & dosage; Hydrogels - chemistry; IDD; In vivo methods and tests; Injectable thermosensitive hydrogel; Intervertebral Disc Degeneration - drug therapy; Intervertebral Disc Degeneration - pathology; Intervertebral discs; Isopropylacrylamide; Musculoskeletal diseases; Nucleus pulposus; Nucleus Pulposus - drug effects; Nucleus Pulposus - metabolism; Pathogenesis; Piperidines - administration & dosage; Piperidines - chemistry; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - antagonists & inhibitors; Protein-tyrosine-phosphatase; Proteins; Pyrimidines - administration & dosage; Pyrimidines - chemistry; Rats; Rats, Sprague-Dawley; Regulatory mechanisms (biology); SHP2; Small molecule drug; Sox9 protein; Temperature; Transfection; Tyrosine
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2020.118891

Intervertebral disc (IVD) degeneration (IDD), a common musculoskeletal disease with limited self-healing ability, is challenging to treat. The development of innovative therapies to reverse IDD depends on the elucidation of its regulatory mechanisms. Therefore, the role of Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2) in the pathogenesis of IDD and the therapeutic effect of its small-molecule inhibitor, SHP099, were investigated. The expression of SHP2 by nucleus pulposus (NP) cells in IVD was investigated in vitro and in vivo, and its molecular mechanism in IDD was explored using transfection technology. Injectable N-isopropylacrylamide-based thermosensitive hydrogels were synthesized for SHP099 delivery. SHP2 was highly expressed in degenerated IVDs, where its overexpression in NP cells inhibited the expression of Sry-related HMG box-9 (Sox9), leading to the decreased expression of key proteins (collagen II and aggrecan) and consequently to IDD. SHP099 reversed the degeneration of NP cells in vitro. Moreover, its administration in rats via the injectable thermosensitive hydrogel had a therapeutic effect on IDD. Our results suggest that SHP2 is a key factor in IDD progression, and SHP099 inhibits both its expression and NP cell degeneration. Therefore, SHP099 delivery via injectable thermosensitive hydrogels is a potential treatment strategy for IDD.