Selecting dietary-derived bioactives which protect cartilage from destruction in osteoarthritis

Osteoarthritis (OA) is a disease that affects the whole joint, with progressive articular cartilage loss. Healthy cartilage must maintain a balance between extracellular matrix synthesis and degradation. Metalloproteinases (Matrix metalloproteinases, MMPs and a disintegrin and metalloproteinase domain with thrombospondin motifs, ADAMTSs) play an important role in cartilage degradation. The collagenases (MMP-1 and MMP-13) and aggrecanases (ADAMTS-4 and ADAMTS-5) are implicated in the development of OA because of their ability to degrade type 2 collagen and aggrecan. This project aims to identify compounds from the diet that could offer protection or slow the progression of OA via collagenase and/or aggrecanase inhibition. Ninety-six dietary derived compounds selected from a Natural Product Library were screened at 10μM for IL1-induced and basal MMP13 inhibition in SW1353 and C28/I2 cells. Several compounds inhibited MMP13 at 10μM in both cell lines. Twenty compounds were selected for study in primary human articular chondrocytes. Of these compounds, apigenin and isoliquiritigenin showed the greatest inhibition of MMP13 while also inhibiting MMP1, ADAMTS4 and ADAMTS5. The effect of apigenin or isoliquiritigenin pretreatment on three pathways implicated in OA, the NFκB, TGFβ and Wnt pathways was analysed. Apigenin and isoliquiritigenin showed differences in the patterns of inhibition in the NFκB and TGFβ pathways. The Human Phospho-Kinase Array Kit was used to perform an unbiased dissection of the kinase pathways affected by apigenin and isoliquiritigenin. Apigenin and isoliquiritigenin had similar effects on many phosphorylation events, however there were kinase phosphorylation events that were specific to either apigenin or isoliquiritigenin treatment. Taken together these data suggest that the chondro-protective gene expression changes seen with apigenin and isoliquiritigenin treatment involves a complex network of signalling pathways that require further characterisation. If these compounds are able to get to the site of OA damage they may prevent progression of OA offering an alternative treatment.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

University of East Anglia

Year dc:date.issued

2015

Author dc:creator

• Green, Jonathan

Language dc:language

en