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p-Synephrine Loaded by Injectable Gelma Hydrogel Ameliorates Cartilage Degeneration in Osteoarthritis by Inhibiting the MAPK and NF-κB Signaling Pathways.

Yiping Yu,Yuanhang Wang,Jing Li,Can Xue,Junfeng Zhang,Pengcheng Gao,Zhi Tao,Zihao Li,Xiaotian Chen,Zhenfei Ding

Published 2025 in Biological and Pharmaceutical Bulletin

ABSTRACT

Inflammation is a key factor that contributes to cartilage degeneration in osteoarthritis (OA). p-Synephrine has anti-inflammatory effects. Nevertheless, the effects of p-synephrine on OA remain to be elucidated. The objective is to explore the effects of p-synephrine on OA. First, cell counting kit-8 (CCK-8) assay and flow cytometry were used to assess the effects of p-synephrine on chondrocyte viability and apoptosis. Then, Western blot and quantitative real time-PCR (qRT-PCR) were employed to determine the expressions of matrix metalloproteinase-1 (MMP-1), MMP-3, and MMP-13, as well as collagen II and aggrecan, in OA chondrocytes induced by interleukin-1β (IL-1β). Furthermore, we created an injectable gelatin methacrylamide (Gelma) hydrogel incorporating p-synephrine and conducted evaluations of its drug release profile and the degradation properties of hydrogels, aiming to optimize the intra-articular application of p-synephrine in the mouse OA model. Finally, cartilage degradation was analyzed using safranine O and fast green staining. In vitro, p-synephrine protected chondrocytes and effectively inhibited IL-1β-induced chondrocyte apoptosis. Moreover, p-synephrine inhibited the expressions of MMP-1, MMP-3, and MMP-13, and increased the expressions of collagen II and aggrecan. p-Synephrine might exert its biological effects by suppressing the mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways. Gelma hydrogels with different degrees of amination could control the release rate of p-synephrine due to differences in their pore structure and degradation rates. Among these, Gelma 90 achieved a more stable and sustained p-synephrine release. In vivo, p-synephrine loaded by injectable Gelma hydrogel thwarted cartilage deterioration. In summary, p-synephrine may exhibit chondroprotective effects by suppressing the MAPK and NF-κB signaling pathways, providing a new treatment for OA.

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