NOD2 attenuates osteoarthritis via reprogramming the activation of synovial macrophages.

OBJECTIVE: Synovial inflammation, which precedes other pathological changes in osteoarthritis (OA), is primarily initiated by activation and M1 polarization of macrophages. While macrophages play a pivotal role in the inflammatory process of OA, the mechanisms underlying their activation and polarization remain incompletely elucidated. This study aims to investigate the role of NOD2 as a reciprocal modulator of HMGB1/TLR4 signaling in macrophage activation and polarization during OA pathogenesis. DESIGN: We examined NOD2 expression in the synovium and determined the impact of NOD2 on macrophage activation and polarization by knockdown and overexpression models in vitro. Paracrine effect of macrophages on fibroblast-like synoviocytes (FLS) and chondrocytes was evaluated under conditions of NOD2 overexpression. Additionally, the in vivo effect of NOD2 was assessed using collagenase VII induced OA model in mice. RESULTS: Expression of NOD2 was elevated in osteoarthritic synovium. In vitro experiments demonstrated that NOD2 serves as a negative regulator of HMGB1/TLR4 signaling pathway. Furthermore, NOD2 overexpression hampered the inflammatory paracrine effect of macrophages on FLS and chondrocytes. In vivo experiments revealed that NOD2 overexpression mitigated OA in mice. CONCLUSIONS: Supported by convincing evidence on the inhibitory role of NOD2 in modulating the activation and M1 polarization of synovial macrophages, this study provided novel insights into the involvement of innate immunity in OA pathogenesis and highlighted NOD2 as a potential target for the prevention and treatment of OA.

Osteoporosis Diagnostic Model Using a Multichannel Convolutional Neural Network Based on Quantitative Ultrasound Radiofrequency Signal.

Quantitative ultrasound (QUS) is a promising screening method for osteoporosis. In this study, a new method to improve the diagnostic accuracy of QUS was established in which a multichannel convolutional neural network (MCNN) processes the raw radiofrequency (RF) signal of QUS. The improvement in the diagnostic accuracy of osteoporosis using this new method was evaluated by comparison with the conventional speed of sound (SOS) method. Dual-energy X-ray absorptiometry was used as the diagnostic standard. After being trained, validated and tested in a data set consisting of 274 participants, the MCNN model could significantly raise the accuracy of osteoporosis diagnosis compared with the SOS method. The adjusted MCNN model performed even better when adjusted by age, height and weight data. The sensitivity, specificity and accuracy of the adjusted MCNN method for osteoporosis diagnosis were 80.86%, 84.23% and 83.05%, respectively; the corresponding values for SOS were 50.60%, 73.68% and 66.67%. The area under the receiver operating characteristic curve of the adjusted MCNN method was also higher than that of SOS (0.846 vs. 0.679). In conclusion, our study indicates that the MCNN method may be more accurate than the conventional SOS method. The MCNN tool and ultrasound RF signal analysis are promising future developmental directions for QUS in screening for osteoporosis.

MiR-92a/KLF4/p110δ regulates titanium particles-induced macrophages inflammation and osteolysis.

As total joint replacement is widely applied for severe arthropathy, peri-prosthetic aseptic loosening as one of the main causes of implant failure has drawn wide attention. Wear particles such as titanium particles (TiPs) derived from prosthesis can initiate macrophages inflammation and sequentially activate osteoclasts, which results in bone resorption and osteolysis for long-term. Therefore, inhibiting wear particles induced macrophages inflammation is considered as a promising therapy for AL. In this research, we found that the inhibition of p110δ, a member of class IA PI3Ks family, could significantly dampen the TiPs-induced secretion of TNFα and IL-6. By the transfection of siRNA targeting p110δ, we confirmed that p110δ was responsible for TNFα and IL-6 trafficking out of Golgi complex without affecting their expression in TiPs-treated macrophages. As the upstream transcription-repressor of p110δ, Krüppel-like factor 4 (KLF4), targeted by miR-92a, could also attenuate TiPs-induced inflammation by mediating NF-κB pathway and M1/M2 polarization. To further ascertain the roles of KLF4/p110δ, TiPs-induced mice cranial osteolysis model was established and vivo experiments validated that KLF4-knockdown could exacerbate TiPs-induced osteolysis, which was strikingly ameliorated by knockdown of p110δ. In summary, our study suggests the key role of miR-92a/KLF4/p110δ signal in TiPs-induced macrophages inflammation and osteolysis.

Osteoporosis Diagnosis Based on Ultrasound Radio Frequency Signal via Multi-channel Convolutional Neural Network.

Osteoporosis is a metabolic osteopathy syndrome, and the incidence of osteoporosis increases significantly with age. Currently, bone quantitative ultrasound (QUS) has been considered as a potential method for screening and diagnosing osteoporosis. However, its diagnostic accuracy is quite low. By contrast, deep learning based methods have shown the great power for extracting the most discriminative features from complex data. To improve the osteoporosis diagnostic accuracy and take advantages of QUS, we devise a deep learning method based on ultrasound radio frequency (RF) signal. Specifically, we construct a multi-channel convolutional neural network (MCNN) combined with a sliding window scheme, which can enhance the number of data as well. By using speed of sound (SOS), the quantitative experimental results of our preliminary study indicate that our proposed osteoporosis diagnosis method outperforms the conventional ultrasound methods, which may assist the clinician for osteoporosis screening.