HKBU-led research team discovers novel aptamer therapy that alleviates arthritis by targeting liver-derived protein
Arthritis is a prevalent health problem worldwide and a silent health threat in Hong Kong. It encompasses more than 100 different conditions, commonly characterised by pain and inflammation in one or more joints. The two most common forms are rheumatoid arthritis (RA) and osteoarthritis (OA). Although they share several pathological features, their underlying molecular mechanisms remain poorly understood.
To address this unresolved clinical challenge, a research team led by Professor Lyu Aiping, Vice-President (Research and Development) and Dean of the Graduate School, has successfully developed a novel therapeutic strategy for RA and OA using the ApmCRP3 aptamer.
The liver is the principal site of production and release of various factors that influence joint health, including C-reactive protein (CRP). CRP levels are elevated in patients with both RA and OA. CRP exists in two distinct forms: native pentameric C-reactive protein (nCRP) and monomeric C-reactive protein (mCRP). The respective roles of these two forms of CRP in arthritis have long remained controversial.
The researchers genetically modified mice so that their liver cells were unable to produce CRP. They then established separate mouse models that mimicked RA and OA. Compared with control mice, the genetically modified mice developed milder disease. In the RA model, they exhibited less joint swelling, synovial hyperplasia and cartilage erosion, as well as lower levels of inflammatory markers in the blood. In the OA model, they developed fewer osteophytes, less synovial hyperplasia and reduced cartilage damage. These findings support the conclusion that liver-derived CRP actively contributes to disease progression, rather than merely increasing passively in response to inflammation.
The study also showed that mCRP stimulated joint synovial cells to proliferate, invade surrounding tissues and resist cell death. It also drove immune cells towards a pro-inflammatory state and damaged key components required for cartilage formation. In contrast, nCRP produced little to no harmful effect and, in some circumstances, appeared to exert a mildly protective effect.
Based on these findings, the research team used a screening technique known as systematic evolution of ligands by exponential enrichment (SELEX) to identify the ApmCRP3 aptamer. This aptamer binds effectively and specifically to mCRP without affecting nCRP.
Further experiments using mouse models of RA and OA demonstrated that ApmCRP3 significantly reduced the severity of arthritis, alleviated bone erosion and improved the health of joint tissues. More importantly, the aptamer performed better than an existing CRP-stabilising compound, with no evidence of toxicity to the liver, kidneys or other major organs.
Professor Lyu said: “ApmCRP3 effectively blocks the damaging effects of mCRP. It prevents excessive proliferation and tissue invasion by joint synovial cells, reduces inflammatory activity in immune cells, and enables cartilage cells to resume healthy tissue synthesis.”
He added that, by selectively neutralising the harmful form of mCRP, the study is helping to pioneer a novel therapeutic approach to arthritis. ApmCRP3 offers new hope to patients with RA and OA, opens up a promising new direction for the development of aptamer-based therapies, and has the potential to reshape arthritis treatment strategies worldwide.
Full paper on Journal of Orthopaedic Translation: https://pubmed.ncbi.nlm.nih.gov/41031135
Professor Lyu’s research profile: https://scholars.hkbu.edu.hk/en/persons/AIPINGLU
Professor Lyu Aiping
School of Chinese Medicine
