Kartogenin hydrolysis product 4-aminobiphenyl distributes to cartilage and mediates cartilage regeneration

Abstract

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.

Molecular Insights Into Lysyl Oxidases in Cartilage Regeneration and Rejuvenation

“…Until now, the etiology and pathophysiology of OA have not been well documented. Various treatments, such as cellular therapies (Fu et al, 2014;Lee and Wang, 2017;Lin et al, 2017;Teo et al, 2019;Xu et al, 2019), administration of certain drugs or chemicals (Zhang et al, 2016(Zhang et al, , 2019Yao et al, 2019), therapeutic surgeries (Chen Y. et al, 2015), and biofabrication approach (Tatman et al, 2015;Onofrillo et al, 2018;Lee et al, 2019), have been intensely studied and tested in various preclinical studies and clinical trials during recent decades (Lee and Wang, 2017;Zhang et al, 2019). However, several hurdles are required to be addressed for therapeutic optimization before clinical translation.…”

Stem Cells Promote the Regeneration of Knee Joint Degenerative Bone and Articular Cartilage

“…It often manifests as pain when going up and down stairs, walking, unstable and bumpy, and poor flexion and extension. In severe cases, loss of joint function may occur, leading to loss of labor and living ability [ 9 , 10 ]. There are about 250 million patients with knee pain around the world, and the elderly account for 30% of those with knee pain.…”

A low dose cell therapy system for treating osteoarthritis: In vivo study and in vitro mechanistic investigations

“…KEGG pathway analysis showed enrichment for ribosome biogenesis, cell cycle, and PI3K-Akt signaling pathway in 3D MSCs. The enrichment of PI3K-Akt signaling pathway possibly points to a mechanism by which MSCs in microniches may undergo increased proliferation and improve the repair of OA injury [ [72] , [73] , [74] ]. Chondrocytes in the 3D group showed enrichment for focal adhesion and N-Glycan biosynthesis pathway, possibly suggesting better phenotype maintenance.…”