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Intra-articular sustained-release of pirfenidone as a disease-modifying treatment for early osteoarthritis

Bioactive Materials 2024年第9期39卷 255-272页

作者： Xiaobo Zhu Mingde Cao Kejia Li Yau-Tsz Chan Hon-Fai Chan Yi-Wah Mak Hao Yao Jing Sun Michael Tim-Yun Ong Kevin Ki-Wai Ho Chien-Wei Lee Oscar Kuang-Sheng Lee Patrick Shu-Hang Yung Yangzi Jiang Institute for Tissue Engineering and Regenerative Medicine School of Biomedical SciencesFaculty of MedicineThe Chinese University of Hong KongShatinHong Kong Special Administrative Region of ChinaChina School of Biomedical Sciences Faculty of MedicineThe Chinese University of Hong KongShatinHong Kong Special Administrative Region of Chin1China Department of Orthopaedics&Traumatology Faculty of MedicineThe Chinese University of Hong KongPrince of Wales HospitalShatinHong Kong Special Administrative Region of Chin1China Center for Neuromusculoskeletal Restorative Medicine Hong Kong Special Administrative Region of Chin1China Key Laboratory for Regenerative Medicine Ministry of EducationSchool of Biomedical SciencesFaculty of MedicineThe Chinese University of Hong KongHong Kong Special Administrative Region of Chin1China Department of Orthopaedic Surgery The First Affiliated HospitalSchool of MedicineZhejiang UniversityChina

Osteoarthritis(OA)is a major clinical challenge,and effective disease-modifying drugs for OA are still lacking due to the complicated pathology and scattered treatment *** early treatments are urgently needed to prevent OA *** excessive amount of transforming growth factorβ(tgfβ)is one of the major causes of synovial fibrosis and subchondral bone sclerosis,and such pathogenic changes in early OA precede cartilage *** we report a novel strategy of intra-articular sustained-release of pirfenidone(PFD),a clinically-approved tgfβinhibitor,to achieve disease-modifying effects on early OA *** found that PFD effectively restored the mineralization in the presence of excessive amount of tgfβ1(as those levels found in patients’synovial fluid).A monthly injection strategy was then designed of using poly lactic-co-glycolic acid(PLGA)microparticles and hyaluronic acid(HA)solution to enable a sustained release of PFD(the“PLGA-PFD+HA”strategy).This strategy effectively regulated OA progression in destabilization of the medial meniscus(DMM)-induced OA mice model,including preventing subchondral bone loss in early OA and subchondral bone sclerosis in late OA,and reduced synovitis and pain with cartilage preservation *** finding suggests the promising clinical application of PFD as a novel disease-modifying OA drug.

关键词： tgfβ1 signaling Osteoarthritis Subchondral bone Pirfenidone DMOAD

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SND1 acts as a novel gene transcription activator recognizing the conserved Motif domains of Smad promoters, inducing tgfβ1 response and breast cancer metastasis

SND1 acts as a novel gene transcription activator recognizin...

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第十一届全国免疫学学术大会

作者： Yu Lin Di Yanbo Xin Lingbiao Ren Yuanyuan Liu Xin Sun Xiaoming Zhang Wei Yao Zhi Yang Jie Tianjin Medical University

Target: As an AEG-1/MTDH/LYRIC-binding protein, SND1 is upregulated in numerous human cancers where it has been assigned multiple functional roles. Methods: In the present study, we use Ch IP-chip, EMSA assays to analyze the promoter binding affinity of SND1 protein with the Smad gene promoters. Immunoprecipitation, GST-pulldown assays were used to detect the parter transfactors of SND1, Q-RT-PCR array, western blot were used to confirm the transcription activation function of SND1 to Smad genes. Results: We discovered that SND1 was upregulated in breast cancer tissues, particularly the tissues from patients with distant metastases. The underlying molecular mechanisms demonstrated a novel role of SND1 in regulating the activity of transforming growth factor β1(tgfβ1) signaling pathway, which promotes metastasis in breast cancer. We illustrated that SND1 physically associated with and recruited the histone acetylase(HAT) GCN5 to the promoter regions of Smad2/3/4, and consequently enhanced the gene transcriptional activation of Smad2/3/4, which are essential regulators in the downstream of tgfβ1 pathway. The EMSA experiment further verified that SND1 could recognize the conserved domains(motifs 1, 2) in the promoter regions of the Smad genes. GST pulldown assays indicated that it was the Tudor domain of SND1 responsible for the recruitment of GCN5 and increasing histone H3K9 acetylation. Conclusion: Consistent with these results, the loss-of-function of SND1 reduced the protein level of Smads and the phosphorylation of R-Smads, subsequently attenuated the formation and translocation of R-Smad/Co-Smad complex to the nucleus, as a result, inhibited tgfβ signaling activation.

关键词： SND1 breast cancer histone acetylase tgfβ1 signaling metastasis

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