Doctoral defence: Priya Kulkarni “Osteoarthritis pathogenesis: an immunological passage through synovium-synovial fluid axis”

On 27 October at 15:00 Priya Kulkarni will defend her doctoral thesis “Osteoarthritis pathogenesis: an immunological passage through synovium-synovial fluid axis”.

Supervisors:
Professor Aare Märtson, University of Tartu
Professor Sulev Kõks, University of Tartu
former visiting lecturer Abhay Madhukar Harsulkar, University of Tartu

Opponent:
Professor Kalervo Väänanen, University of Turku (Finland)

Summary

Osteoarthritis (OA) is the most common joint disease, which has no pathogenetic cure to date. The major challenges in developing effective therapies are, heterogenous nature and obscure pathology of OA. Conventionally known as ‘aging disease’, OA is increasingly accepted as a complex disease with an implication of chronic-low-grade inflammation. More illumination is needed on the involved inflammatory mechanism.

The present thesis was aimed to evaluate inflammatory mechanism revolving around the synovium-synovial fluid (SF) axis, which are the main inflammation sites in OA pathology. In this regard, particularly SF analysis is limited to understand a molecular make-up of the fluid and there is a wider scope to assess its functional involvement. Therefore, the attempt was to investigate a ‘performance-based involvement’ of SF by decoding the molecular signaling.

A multilevel analysis was done using OA affected synovium biopsies, SF and osteophyte samples. Also, cell-based assays were performed using human monocyte cell lines (THP1 and U937) and human hematopoietic stem cells. Proteome analysis and SF immunophenotyping was performed to support the outcomes from the biological assays. Synovium gene expression study showed a persistent nature of inflammation in OA joints. Higher inflammation in early stage provides a necessary impetus for accelerated cartilage-loss at later stages. SF samples of all OA stages, when incubated with THP1 and U937 cells, was able to induce inflammation in the cells. In the same experimental design, we showed that OA SF can induce immune cell differentiation and act as a niche by providing an essential microenvironment, which enable immune cells to be functionally active and for contributing to aggravate and maintain inflammation. Proteome analysis of SF revealed many proteins in abundance, which can induce immune cell differentiation as was observed. Finally, RNA-seq analysis of osteophytes was performed to investigate molecular and cellular events in it, especially in the context of OA pathology. Functional analysis of the gene expression patten, revealed an on-going active bone remodelling and close involvement of mast cells in the process, which is a new dimension of OA pathology and should prove worthy for taking into consideration for designing appropriate therapies.