Targeting Rac1 via Microparticle-based Drug Delivery System Protects OA Cartilage in Vivo-Prof. Ouyang Hongwei¡¯s Group Identified New Pathophysiological Mechanism and Treating Method of OA
2016-01-22 OnClick: 2955
The small GTPase Rac1, also known as Ras-related C3 botulinum toxin substrate 1, is as a positive regulator of chondrocyte hypertrophy and endochondral ossification during bone formation, processes that are recapitulated in osteoarthritis (OA). A new research led by Professor Hong Wei Ouyang shows that inhibition of the aberrant activation of Rac1 in OA, using a novel drug delivery approach, could have therapeutic potential in this disease.
In the study published in Annals of the Rheumatic Diseases (2015 Jan;74(1):285-93.), the authors demonstrated in vitro that
, although Rac1 is abundantly expressed in both normal and OA cartilage, its activated form is overexpressed in the latter. Furthermore, treatment of chondrocytes with IL-1βupregulated Rac1 activity. Tellingly, the introduction of active Rac1 into chondrocytes led to increased expression of genes related to matrix degradation and hypertrophy such as MMP13, ADAMTS -5 and COL X in part via the β-catenin pathway, adding to the evidence implicating Wnt signaling in cartilage destruction in OA. In a mouse model, intra-articular injection of DN-Rac1 lentivirus into OA joints downregulated Rac1 and had a protective effect on cartilage, whereas CA-Rac1 lentivirus elevated Rac1 activity and accelerated OA progression and cartilage degradation.
Having shown the therapeutic effect of Rac1 inhibition in vivo, the investigators set about solving the problem of maintaining an effective intra-articular concentration of the Rac1 inhibitor, by exploring the potential of a novel drug-delivery approach. The drug was encapsulated in polymeric chitosan microspheres of ~100μm in size. In mice, weekly intra-articular injection of hyaluronic acid containing the microspheres into OA joints led to decreased cartilage destruction and delayed OA development.
This work was highlighted in Nature Review Rheumatology
, and won the Sanofi Award for Excellence in Cartilage Research in the 11th World International Cartilage Repair Society. The project is supported by National Key Scientific Research Project, National Natural Science Foundation of China, Zhejiang Province Public Welfare Fund and so on.