Combating Osteoarthritis: New Insights in Cellular Research
- UM Research
- May 9
- 3 min read
Osteoarthritis (OA) is a degenerative joint condition characterised by progressive cartilage degradation, joint stiffness, and pain, often leading to disability. While the definitive treatment for advanced OA remains surgical joint replacement, early-stage management typically includes physiotherapy, pain relief medications, hyaluronic acid injections, or platelet-rich plasma (PRP) therapy. These non-surgical approaches aim to alleviate symptoms and delay surgery but do not reverse joint damage.
Recognising the critical role of fibrosis in joint stiffness and degeneration among OA patients, Professor Dr. Ali Mohammad Sharifi of Universiti Malaya's (UM) Faculty of Medicine has conducted extensive research to uncover the cellular mechanisms underlying synovial fibrosis. His groundbreaking work aims to develop therapeutic strategies to restore joint function and slow OA progression. The research targets explicitly the HIF-1α transcription factor, which is implicated in the pathological transformation of fibroblast-like synoviocytes (FLS) into myofibroblasts and its downstream TGFβ/ALK/SMAD/CTGF signalling pathway.
"HIF-1α responds to hypoxic stress in osteoarthritic joints, promoting fibrotic changes and pro-fibrotic gene expression. The TGFβ/ALK/SMAD/CTGF pathway further drives myofibroblast formation and excessive extracellular matrix (ECM) production, accelerating joint degeneration. By targeting both HIF-1α and the TGFβ/ALK/SMAD/CTGF signaling cascade, we aim to modulate the hypoxic response and inhibit fibroblast activation. This dual approach offers a promising strategy to combat fibrosis and slow OA progression," Prof. Dr. Sharifi explained.
For decades, OA research has predominantly focused on cartilage degradation and the role of chondrocytes, as cartilage breakdown is the hallmark of the disease. However, fibrosis within osteoarthritic joints and the role of FLS in promoting fibrotic changes have been relatively underexplored.
"FLS plays a critical role in synovial fibrosis by producing ECM components and inflammatory cytokines that amplify the fibrotic response. Viewing FLS as active contributors to fibrosis, rather than passive bystanders, represents a relatively new perspective. This shift is driving renewed interest in targeting FLS in OA fibrosis research," he added.
Prof. Dr. Sharifi's research, conducted at the National Orthopaedic Centre of Excellence for Research and Learning (NOCERAL), is structured into three strategic phases:
Phase 1: Comparing the phenotypic differences and fibrotic gene expression profiles of synovial tissues from OA patients and non-OA controls.
Phase 2: Employing advanced techniques such as western blotting and Masson Trichrome staining, combined with CRISPR-Cas9 gene editing, to silence HIF-1α in OA-FLS and study its effects.
Phase 3: Evaluating the impact of silencing downstream molecules, including SMAD1, SMAD5, SMAD8, SMAD2, SMAD3, and CTGF, to assess their contributions to fibrosis.
Despite the potential benefits, Prof. Dr. Sharifi acknowledged the challenges of targeting the HIF-1α pathway due to its critical roles in physiological processes:
Vascularization: HIF-1α inhibition could impair the production of vascular endothelial growth factor (VEGF), potentially reducing blood vessel formation and hindering joint repair.
Immune Response: Modulating HIF-1α may alter immune cell activation and inflammation, increasing the risk of infection or promoting autoimmune conditions.
Cellular Metabolism: Blocking HIF-1α could disrupt glycolysis, negatively affecting cellular energy metabolism, particularly under hypoxic conditions in joint tissues.
Given these risks, Prof. Dr. Sharifi emphasised the importance of a multi-stage development process to ensure safety and efficacy before introducing new therapies. Following confirmation of the research hypothesis, the steps include:
Preclinical Development: Refining and testing HIF-1α-targeted treatments in animal models of OA to optimize dosage, delivery methods, and potential combination therapies.
Drug Development: Conducting pharmacokinetic studies and safety assessments to determine the most suitable drug formulation for human use.
Clinical Trials: These trials will start with early-phase trials to evaluate safety and tolerability, followed by larger, multi-centre trials to confirm therapeutic benefits and efficacy.
Prof. Dr. Sharifi's research offers a promising pathway toward developing innovative therapies for OA by addressing the often-overlooked contribution of fibrosis. Through a comprehensive understanding of the cellular mechanisms driving synovial fibrosis, his work may pave the way for transformative treatments that restore joint function and improve the quality of life for millions of OA patients worldwide.
#Osteoarthritis #JointHealth #MedicalResearch #Fibrosis #HealthcareInnovation #PainRelief #ArthritisAwareness #ScienceForHealth #Orthopedics #MedicalBreakthroughs #ChronicPain #HealthTech #OAResearch #JointCare #FutureOfMedicine #Arthritis
Researcher Featured:
Professor Dr Ali Mohammad Sharifi
Department of Orthopaedic Surgery
Faculty of Medicine, Universiti Malaya
For inquiries, please contact:
T: 03-79672693
Author:
Mr. Wong Zhi Yong
A passionate medical student who seeks a balance between science and writing. From dissecting the intricacies of the human body to weaving narratives, I am intrigued by medicine and the written word.
Image by:
BruceBlaus, CC BY-SA 4.0 <https://creativecommons.org/licenses/by-sa/4.0>, via Wikimedia Commons
Copyedit:
Siti Farhana Bajunid Shakeeb Arsalaan Bajunid, Assistant Registrar, UM
Nurhazrin Zanzabir, Assistant Administrative Officer, UM
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