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Rationale The small molecule Kartogenin (KGN) promotes cartilage regeneration in osteoarthritis (OA) by activating stem cells differentiation, but its pharmacological mode-of-action remains unclear. KGN can be cleaved into 4-aminobiphenyl (4-ABP) and phthalic acid (PA) following enzymolysis of an amide bond. Therefore, this study investigated whether 4-ABP or PA exerted the same action as KGN.Methods KGN, 4-ABP and PA were analyzed in cartilage of mice after oral, intravenous or intra-articular administration of KGN by liquid chromatography-mass spectrometry method. Their effect on proliferation and chondrogenic differentiation of mesenchymal stem cells (MSC) was evaluated in vitro. Furthermore, their effect on cartilage preservation was tested in mice OA model induced by destabilization of medial meniscus. OA severity was quantified using OARSI histological scoring. Transcriptional analysis was used to find the possible targets of the chemicals, which were further validated.Results We demonstrated that while oral or intra-articular KGN delivery effectively ameliorated OA phenotypes in mice, only 4-ABP was detectable in cartilage. 4-ABP could induce chondrogenic differentiation and proliferation of MSC in vitro and promote cartilage repair in OA mouse models mainly by increasing the number of CD44+/CD105+ stem-cell and prevention of matrix loss. These effect of 4-ABP was stronger than that of KGN. Transcriptional profiling of 4-ABP-stimulated MSC suggested that RPS6KA2 and the PI3K-Akt pathway were 4-ABP targets; 4-ABP could activate the PI3K-Akt pathway to promote MSC proliferation and repair OA injury, which was blocked in RPS6KA2-knockdown MSC or RPS6KA2-deficient mice.Conclusion 4-ABP bio-distribution in cartilage promotes proliferation and chondrogenic differentiation of MSC, and repairs osteoarthritic lesions via PI3K-Akt pathway activation.

Aim: To assess cartilage-derived stem/progenitor cells (CSPCs) in osteoarthritis (OA) by employing mRNA-miRNA-circRNA-lncRNA network biology approach. Methods: Differentially expressed (DE) RNAs in CSPCs from 2-/4-/8-month-old STR/Ort and CBA mice were identified to construct networks via RNA sequencing. Results: Compared with age-matched CBA mice, 4-/8-month-old STR/Ort mice had cartilage lesions and their CSPCs exhibited lower proliferative and differentiation capacity (decreased CD44 and CD90), and identified 7082 DE RNAs in STR/Ort mice were associated with strain differences or OA progression. OA-related core RNAs were identified via the networks constructed with the predominant DE RNAs, which were involved in the signaling pathways (NF-κB/MAPK/Hippo/Wnt/TGF-β/cytoskeleton organization). The core RNAs (miR-322-5p/miR-493-5p/miR-378c/CPNE1/Cdh2/PRDM16/CTGF/NCAM1) were validated in CSPCs from OA patients. Conclusion: RNA-based networks identifying core RNAs and signaling pathways contribute to CSPC-dependent OA mechanisms.

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