PB0161 - The potential role of Matrix Metalloproteinases in the onset of Haemophilic Arthropathy

Sunday, June 25, 2023

18:30 – 19:30 ET

Room: Exhibition

Co-Author(s)

Wayne Hauw, MBBs, FRCPA, FRACP

PhD student, Clinical Haeamtologist
Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Victoria, Australia
Melbourne, Victoria, Australia

Presenting Author(s)

Harshal Nandurkar, MD, PhD, FRACP, FRCPA (he/him/his)

Director of Cancer Program, Alfred Health. Head of the Australian Centre for Blood Diseases
Alfred Health and Monash University
Melbourne, Victoria, Australia

Co-Author(s)

MS

Maithili Sashindranath

Senior Scientist and Deputy Lab Head
Australian Centre for Blood Diseases, Monash University
Melbourne, Victoria, Australia
JC

Joanna Chia

Research Assistant
Australian Centre for Blood Diseases
Melbourne, Victoria, Australia
CS

Carly Selan

Research Assistant
Australian Centre for Blood Diseases, Monash University
Melbourne, Victoria, Australia
IC

Ilaria Calvello

Research Assistant
Australian Centre for Blood Diseases, Monash University
Melbourne, Victoria, Australia
AV

Amy Vuong

Research Assistant
Australian Centre for Blood Diseases
Melbourne, Victoria, Australia
IS

Ioanna Savvidou

Senior Research Fellow
Alfred Health, Monash University
Melbourne, Victoria, Australia

Background: Joint bleeding in people with haemophilia leads to haemophilic arthropathy (HA), a degenerative joint disease with devastating impact on mobility and quality of life.
Matrix metalloproteinases (MMPs) are key players in arthritis. Their role in HA development remain uncharacterised to date. Critical for activation of MMPs including MMP2 and MMP14 are members of the fibrinolytic pathway uPA/tPA (urokinase and tissue plasminogen activator), and their target plasminogen.

Aims: To characterise the involvement of MMPs in HA development and study effects of MMP blockade as an adjuvant treatment for HA.

Methods: We simulated HA in knee joints of haemophilic mice by inducing up to two injuries over 4 weeks. Joint tissues were harvested at 2- and 4-weeks after injury for assessment.
The extent of inflammation and joint damage were evaluated using histological staining techniques and by assessing joint swelling and gait changes in mice.
Gelatin zymography, western blotting and ELISA were used to assess MMP and plasminogen activation.
The effect of MMP inhibition was studied by subcutaneous injection of Ilomastat (GM 6001; a pan MMP inhibitor; 50mg/kg; 3 doses).

Results: Knee injuries induce HA in mice over a 4-week period and is assessed by changes in gait, knee swelling, inflammatory infiltrates and synovial proliferation in situ. We observed significant activation and upregulation of gelatinases MMP2 and MMP-14 in injured knee joints compared to uninjured joints at 2 and 4 weeks post-injury (Fig 1).
MMP14 activates MMP2, and MMP14 is induced by plasminogen activation. Accordingly, there was significant upregulation of uPA 2 weeks after knee injury.
Administration of Ilomastat resulted in significant reduction of knee inflammation and additionally improved gait.

Conclusion(s): The plasmin-MMP axis has a critical role in the development of HA. MMP blockade is an attractive novel therapeutic approach that may synergise with current therapies to prevent recurring joint damage.