Invited speaker: Ioannis Kanakis, BSc, MSc, PhD, FHEA, Assoc.
Professor in Clinical Biochemistry, Chester Medical School, University of Chester, UK
Date: Wednesday, May 28, 2025
Time: 13.00 (Greek hour)
Place: https://upatras-gr.zoom.us/j/94321665523?pwd=kGKuP4T6XtmfSjrr3lb5xe1Fpa6fsv.1
TITLE: [-1A]TIMP-3: a TIMP3 variant as an effective disease-modifying agent against osteoarthritis.
Abstract
Osteoarthritis is the most common degenerative joint disease and a world-wide healthcare burden. A key feature of osteoarthritis is the gradual loss of articular cartilage and bone deformation, resulting in the impairment of joint function. The primary cause of cartilage destruction is considered to be the presence of elevated proteolytic enzymes, such as matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) proteases.
Although the broad-spectrum inhibitors were chondro-protective in animal models, clinical trials disclosed lack of efficacy and safety concerns. We have focused on examining the actions of native, biological inhibitors, namely the tissue inhibitors of MMP (TIMPs). Amongst all four TIMPs, TIMP-3 exerts the broadest inhibitory effect on members of the metzincin family. Mouse models of osteoarthritis are proving critical in advancing our understanding of the underpinning molecular mechanisms. The STR/ort mouse is a well-recognized model which develops a natural form of osteoarthritis very similar to the human disease.
During the last decade, we have focused on a variant of tissue inhibitor of metalloproteinase-3 ([-1A]TIMP-3) which selectively inhibits ADAMTSs but not MMPs due to a single alanine N-terminal addition. Using the background of STR/Ort mice, which develop spontaneous OA, we generated transgenic mice that overexpress [-1A]TIMP-3, either ubiquitously or conditionally in chondrocytes. Our results provided evidence that [-1A]TIMP-3–mediated inhibition of aggrecanases can protect against
cartilage degradation in a naturally occurring STR/ort mouse model of OA, and they highlight a novel role that aggrecanase inhibition may play in increased bone mass. In addition, we showed that after surgically induced joint instability, TIMP3 overexpression proved to be less protective in cartilage destruction than [-1A]TIMP-3 at late stages of OA.
Furthermore, we also demonstrated that [-1A]TIMP-3 can protect against temporomandibular joint osteoarthritis (TMJ-OA), a painful disease that causes masticatory dysfunction, with incomplete appreciation of aetiology.
Demitrios H. Vynios
Professor of Connective Tissue Biochemistry
Biochemistry, Biochemical Analysis & Matrix Pathobiochemistry Research Group
Department of Chemistry
University of Patras,
26504 Patras, Greece
Tel.: GR+2610997914
Prof. I. Kanakis, Abstract