Rogers N1, Julovi S1
1Westmead Institute For Medical Research, Westmead, Australia
Background: Osteoarthritis (OA) is the most common joint disease and a leading cause of pain and disability. Chronic kidney disease (CKD) increases the risk of OA and worsens prognosis. Standard analgesics are poorly tolerated in CKD patients, therefore there is an urgent clinical need to find better therapies. The matrix protein thrombospondin-1 (TSP1) is upregulated in CKD, but its role in OA is unexplored.
Method: We have developed a world-first pre-clinical model of combined OA (DMM:destruction of the medial meniscus) and CKD (5/6 nephrectomy:5/6-Nx). Age-matched male C57BL/6 (WT) and TSP1KO (B6 background) mice were subjected to DMM and/or 5/6-Nx surgery or sham-operation. Blood pressure (BP) and weight were monitored weekly. At 12 weeks, we performed cutting-edge micro-CT and MRI imaging to assess bone volume, joint integrity and blood flow. Phenotyping of kidney and joints was also performed.
Results: Both WT and TSP1KO DMM-5/6-Nx mice demonstrated equivalent changes in systolic and diastolic BP, impaired serum creatinine and polyuria. The DMM-5/6-Nx model led to increased plasma TSP1 in WT mice only. There were equivalent elevations in plasma alkaline phosphatase, calcium and phosphate, but suppressed parathyroid hormone levels in WT and TSP1KO DMM-5/6-Nx mice. Imaging of WT DMM-5/6-Nx mice demonstrated sclerosis of the medial tibial plateau, limited blood flow, increased cartilage degeneration and synovitis in the affected knee, which was worse than WT DMM or 5/6-Nx alone. These results were mitigated in TSP1KO mice. Histologically, TSP1KO DMM-5/6-Nx mice maintained subchondral bone marrow and cartilage thickness, with reduced osteophyte formation.
Conclusion: These data establish CKD as a risk factor for concomitant OA and demonstrate that inhibiting TSP1 signalling is a potential therapeutic opportunity to prevent OA.
Natasha Rogers is an academic Transplant Nephrologist and Director of the Clinical Islet Transplant Program at Westmead Hospital. She is also an Associate Professor and NHMRC Career Development Fellow at the University of Sydney. She runs a basic science research laboratory at the Westmead Institute for Medical Research, with research interests in dendritic cell biology and mechanisms that promote kidney injury. Natasha is currently Chair of the ANZSN Scientific Program and Awards Committee.