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调节机械生物学作为滑膜纤维化的治疗靶点以恢复关节润滑。

Modulating mechanobiology as a therapeutic target for synovial fibrosis to restore joint lubrication.

作者信息

Bonnevie Edward D, Scanzello Carla R, Mauck Robert L

机构信息

Translational Musculoskeletal Research Center, CMC VA Medical Center, United States; McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, University of Pennsylvania, United States.

Translational Musculoskeletal Research Center, CMC VA Medical Center, United States; Division of Rheumatology, Perelman School of Medicine, University of Pennsylvania, United States.

出版信息

Osteoarthritis Cartilage. 2024 Jan;32(1):41-51. doi: 10.1016/j.joca.2023.09.012. Epub 2023 Oct 20.

DOI:10.1016/j.joca.2023.09.012
PMID:37866546
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10880438/
Abstract

OBJECTIVES

Fibroses are disorders linked to persistence of myofibroblasts due to biochemical (e.g., Transforming growth factor-β) and biophysical cues (e.g., a stiff microenvironment). In the context of osteoarthritis, fibrotic changes in the joint-lining synovium have been linked with disease progression. The objective of this study was to probe synovial fibroblast mechanobiology and how essential functions (i.e., lubrication) are altered in fibrotic environments.

DESIGN

Both ex vivo and in vitro synovium models were assessed for fibrotic and lubrication biomarkers to better understand the role of mechanobiology and lubrication. Additionally, in vitro, work on small molecules targeting mechanobiology was assessed.

RESULTS

Our results indicated that modulating mechanobiology could rescue the fibrotic phenotype instigated by stiffening microenvironment that resulted in altered lubricant expression. A small molecule therapeutic, fasudil, blocked ROCK-mediated contractility and this inhibition of the fibrotic mechano-response of synovial fibroblasts restored proper lubrication function, providing insight into mechanisms of disease progression as well as a new avenue for therapeutic development.

CONCLUSION

This study identifies synovial fibrosis as a condition that potentially has joint-wide deficits through inhibiting lubrication. Additionally, modulating mechanobiology (i.e., ROCK-mediated contractility) may pose a potential target for small molecule therapies that can be delivered to the joint space.

CLASSIFICATION

Applied Biological Sciences.

摘要

目的

纤维化是由于生化信号（如转化生长因子-β）和生物物理信号（如僵硬的微环境）导致肌成纤维细胞持续存在而引发的病症。在骨关节炎的背景下，关节衬里滑膜的纤维化变化与疾病进展相关。本研究的目的是探究滑膜成纤维细胞的力学生物学，以及在纤维化环境中基本功能（即润滑）是如何改变的。

设计

对体外和体内滑膜模型进行纤维化和润滑生物标志物评估，以更好地理解力学生物学和润滑的作用。此外，在体外评估针对力学生物学的小分子研究。

结果

我们的结果表明，调节力学生物学可以挽救由微环境硬化引发的纤维化表型，这种硬化会导致润滑剂表达改变。一种小分子治疗药物法舒地尔可阻断ROCK介导的收缩性，这种对滑膜成纤维细胞纤维化机械反应的抑制恢复了正常的润滑功能，为疾病进展机制以及治疗开发的新途径提供了见解。

结论

本研究确定滑膜纤维化是一种可能通过抑制润滑而导致全关节功能缺陷的病症。此外，调节力学生物学（即ROCK介导的收缩性）可能是可应用于关节腔的小分子疗法的潜在靶点。

分类

应用生物科学

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7027/10880438/eeee22a459c2/nihms-1965950-f0006.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7027/10880438/257db72ee28c/nihms-1965950-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7027/10880438/242d0f21bc5c/nihms-1965950-f0002.jpg
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