Tianhe Zhuifeng Gao reverses inflammatory response and attenuates bone/cartilage destruction in rheumatoid arthritis via PSMC2-RUNX2-COL1A1 axis based on transcriptional regulatory network analysis and experimental validation

<b>Background: </b>Tianhe Zhuifeng Gao (TZG) is an authorized Chinese patent drug with satisfying clinical efficacy, especially for RA patientswith cold-dampness syndrome. However, its underlyingpharmacological mechanisms remain unclear.<b>M</b><b>ethod</b><b>:</b><b> </b>Anti-arthritic effects of TZG were evaluated using an adjuvant-induced arthritis (AIA) ratmodel. Transcriptional regulatory network analysis based on synovial tissuesobtained from AIA rats, combining with our previous analysis based on whole blood samples from RA patients with cold-dampness syndrome were performed to identify involved dominant pathways, which were experimentally verified using AIA-wind-cold-dampness stimulation modified (AIA-M) animal model.<b>R</b><b>esults: </b>TZGtreatmentdramatically attenuated joint injury and inflammatory response in AIA rats, and PSMC2-RUNX2-COL1A1 axis, which was closely associated with bone/cartilage damage, was inferred to be one of therapeutic targets of TZG against RA. Experimentally, TZG displayed obvious pharmacological effects for alleviating the joint inflammation and destruction through reinstating the body weight, reducingthe arthritis score, the limbs diameters, the levels of RF and CRP, and the inflammatory cytokines, recovering the thymus and spleen indexes, diminishing bone and cartilage destruction, as well elevating the pain thresholdsof AIA-M rats. In addition, TZG markedly reversed the abnormal energy metabolism in AIA-M rats through enhancing articular temperature, daily water consumption, and regulating expression levels of energy metabolism parameters and hormones. Moreover, TZG also significantly modulated the abnormal expression levels of PSMC2, RUNX2 and COL1A1 proteins in the ankle tissues of AIA-M rats.<b>C</b><b>onclusion: </b>TZG may exert the bone protective effects in RA therapy via regulating bone and cartilage damage-associated PSMC2-RUNX2-COL1A1 axis.