ABSTRACT
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-κB) 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.
ABSTRACT
Objective To find out if there is any difference in intercondylar fossa width and notch width index (NWI) between tibial intercondylar eminence avulsion fracture and anterior cruciate ligament (ACL) injury.Methods A retrospective study was conducted of the patients who had sought medical attention at Department of Sports Medicine and Adult Reconstructive Surgery,Drum Tower Hospital from June 2014 to May 2018.There were 10 patients with tibial intercondylar eminence avulsion fracture (4 males and 6 females with an average age of 32.7 ± 9.2 years),13 patients with ACL injury (8 males and 5 females with an average age of 31.8 ± 10.9 years) and 22 patients with simple meniscus injury as controls (13 males and 9 females with an average age of 30.9 ± 10.6 years).They all had MRI examination of the knee before surgery.The width of intercondylar fossa and the width and height of bilateral femoral condyles were measured on high resolution images of MRI axial view.NWI was calculated.The 3 groups were compared in intercondylar fossa width and NWI.Results The 3 groups of patients were comparable because there were no significant differences in gender,age,height,weight or BMI between them (P ＞ 0.05).The intercondylar fossa width in the ACL injury group (17.4 ± 3.5 mm) was significantly smaller than that in the avulsion fracture group (20.8 ± 1.1 mm) or in the control group (20.2 ±2.6 mm) (P ＜ 0.05),but no significant difference was detected between the avulsion fracture group and the control group (P ＞ 0.05).NWI in the avulsion fracture group (0.301 ±0.011) was similar to that in the control group (0.280 ±0.039) (P ＞ 0.05) but significantly higher than that in the ACL injury group (0.25 ± 0.05) (P ＜ 0.05).NWI in the ACL injury group was significantly lower than that in the control group (P ＜ 0.05).Conclusions Intercondylar notch stenosis may be a risk factor for ACL injury but may not be associated with tibial intercondylar eminence avulsion fracture.The difference in pathogenesis between tibial intercondylar eminence avulsion fracture and ACL injury may be associated with their difference in NWI.