Dr Tania Crotti

Rheumatoid arthritis is a chronic systemic destructive inflammatory disorder characterised by joint inflammation, synovia hyperplasia and associated destruction of bone and cartilage impacting on joint function. Additionally, nociceptive pain, attributed to the damage to body tissue causes significant morbidity. There is a recognised decrease in the threshold of the sensory nervous system’s response to certain harmful or potentially harmful stimuli threshold (hypernociception) that also
impacts on joint function. Currently, there are few effective treatments that target, inflammation, bone loss and hypernociception. Many disease modifying anti-rheumatic drugs (such as methotrexate) target inflammation, allowing chronic bone erosion to progress. The over -arching aim of the project was to investigate the immunomodulatory and anti-inflammatory properties of parthenolide on s local bone loss and inflammation and the associated hypernociception in an animal model of collagen antibody induced inflammatory arthritis. Clinical Paw
Induction of CAIA resulted in significant redness, tenderness and inflammation in the front and rear paws following LPS administration on day 3. From day 8-10 CAIA mice treated with 4mg/kg PAR had significantly lower paw scores compared to CAIA untreated mice (p<0.05). On day 10 CAIA mice
treated with 1mg/kg PAR also had significantly lower paw scores compared to CAIA untreated mice (p=0.03). Micro-CT BV and PV: Control CAIA CAIA+PAR 1mg/kg CAIA+PAR 4mg/kg
BV measured in the radiocarpal joints was significantly greater in control mice compared to all disease and treatment mice (p<0.0001). Similar to BV, control mice also had a significantly lower PV compared to all disease and treatment groups (p<0.001). Consistent with inflammation present on day 10, CAIA mice treated with 1mg/kg and 4mg/kg PAR showed lower PV measurements compared to CAIA mice.

However, this was not significantly different. Histological evaluation of sagittal sections of the radiocarpal joint and ankle joint showed that CAIA untreated mice had significantly greater scores for cellular infiltration, cartilage and bone degradation and pannus formation compared to non-diseased mice (p<0.0001). Although CAIA mice treated with either 1mg/kg or 4mg/kg PAR exhibited reduced scores for cellular infiltration, cartilage and bone degradation and pannus formation compared to untreated CAIA mice, this was not statistically significant: All CAIA groups had a significantly greater number of TRAP-positive multinucleated cells on the bone surface and within the surrounding soft tissue compared to control mice (p<0.0001 and p=0.0002, respectively). CAIA mice treated with 4mg/kg PAR had a significantly lower number of TRAP-positive multinucleated cells on the bone surface compared to untreated CAIA mice (p<0.05). These mice also had reduced TRAP-positive multinucleated cells within the surrounding soft tissue, however this was not statistically significant. In the rear paws, a significantly greater number of TRAP-positive multinucleated cells was also observed on the bone surface and in the surrounding soft tissue of all disease and treatment groups compared to control mice (p<0.0001). Similar to the front paws, CAIA mice treated with 4mg/kg PAR had a lower number of TRAP-positive multinucleated cells on the bone surface, however this was not statistically significant. Within the surrounding soft tissue CAIA mice treated with both 1mg/kg and 4mg/kg PAR had significantly lower TRAP-positive multinucleated cells compared to CAIA mice (p-0.025 and p-0.0057, respectively). However, there was no significant difference between the two treatment groups. We are currently finalizing immune histochemical analysis of glial activation (astrocyte and microglial) in the brain and spinal cord. This will enable us to determine central involvement of the inflammatory pathway by measuring astroglyosis/microgliosis observed as cellular morphological changes. Glial fibrillary acidic protein (GFAP) as a marker of astrocytes in the mouse CNS and Iba-1as a marker of activated microglia. Current results were presented at the European Calcified Tissue Society PhD Workshop in September 2018. An abstract will also be submitted to the State Australian Rheumatology Association Conference to be held in November 2018. A manuscript is in preparation and will be submitted once the analysis of the CNS has been finalized.