By Sophie Blagg
Prevalence of osteoarthritis (OA) is rising worldwide, with an estimated 250 million people affected.1 OA is generally defined as “a disease that affects all the structures of a joint”,2 with symptoms including; severe pain, swelling, reduced mobility, and joint space narrowing.1 These symptoms lead to a lower quality of life in patients, and confer a large burden onto health-care systems globally.3 This burden is especially prominent in countries with ageing populations, as OA is known to mainly affect individuals over 60 years of age.3 The burden is further exacerbated by an absence of disease-modifying OA drugs (DMOADS) for clinical use; currently treatments are limited to pain management, or joint replacement if possible.4 With the cases of OA rising, and the disabling nature of the disease, this raises the question: what are the barriers to effective treatment?
The lack of effective treatments for OA is due to multiple factors. Firstly, there are many potential risk factors of OA development,5 but specific causes are still debated. To further increase the complexity of treatment, many enzymes known to have a role in cartilage degradation – the main pathological feature of OA – are involved in other bodily processes.6 Consequently, inhibition of these enzymes can lead to detrimental off-target effects. This was observed in animal trials where primates developed increased arterial pressure and other cardiovascular complications in response to a potential therapeutic inhibitor.7 Finally, there is some disagreement about what the end-goals of OA treatment should be. In terms of patient benefit, the main goal of treatment is to reduce pain and increase quality of life. However, pain is subjective and difficult to quantify. On the other hand, halting disease progression necessitates slowing cartilage degradation, but this does not always provide an analgesic effect. Thus, the intended aims of potential treatments are controversial.
To understand OA progression, it is important to understand the main symptom, which is cartilage degradation. Cartilage consists primarily of two components: type II collagen and aggrecan.8 Type II collagen is responsible for the tensile strength of cartilage,9 whereas aggrecan – a large proteoglycan7 – is responsible for compressibility. Aggrecan associates with link proteins and another protein, hyaluronan, to form large protein aggregates.7 These aggregates are highly negatively charged due to the sulphated glycosaminoglycan chains (GAGs) present on the numerous aggrecan monomers.7 GAGs attract positively charged ions and draw water into the cartilage to hydrate the structure, giving it the ability to resist compression.7 Recent research has shown that aggrecan degradation occurs first, followed by type II collagen degradation.5 Aggrecan degradation is a reversible process,10 providing a small window where therapeutic intervention can halt and even reverse the initial stages of OA. Unfortunately, clinical symptoms of OA typically manifest after the disease has progressed relatively far in the joint. When a patient notices pain or stiffness, and wants to access treatment, degradation is usually past the reversible changes.
Cartilage degradation is attributed to the action of matrix metalloproteinases (MMPs) – a large family of enzymes with very similar structures, sharing some homologous domains.11 ADAMTS enzymes are a specific class of MMPs that have been found to target proteoglycans, among which ADAMTS-5 is an enzyme known for its ability to cleave aggrecan.7 Numerous efforts have been made in recent years to try to halt OA progression by inhibiting MMPs. However, aggrecan and other proteoglycans cleaved by ADAMTS proteases are also found in the heart, blood vessels, and brain, where cleavage is essential for normal physiological functions.7 Inhibition of ADAMTS has shown detrimental effects in other organs of the body, resulting in the termination of clinical trials of potential drugs.7 Research is currently making more headway by focusing on designing specific, small molecule, inhibitors that target exosites, which are regions away from the active site.12 Exosites are generally less conserved between enzymes of the same family, allowing for greater specificity of inhibitors. Furthermore, exosites implicated in aggrecan cleavage may differ from exosites needed for other substrate cleavage by the same enzyme; this would allow for specific substrate cleavage inhibition.13
However, with ongoing research into pharmacological approaches to inhibit cartilage degradation, has a major part of OA treatment been overlooked? Some DMOADS have been successful in reducing cartilage degradation; for example, compound GLPG1972.14 Disappointingly, some promising compounds show little effect on pain management.15 Many patients still suffer from mechanical allodynia – pain in response to a normally unpainful stimulus16 – after treatment. The problem with this is that although the progression of the disease may be halted, patients are less likely to follow prescription instructions if the drug is not improving symptoms of pain. Cartilage itself has no blood vessels or neurons,4 and therefore cannot detect painful stimuli. It is the surrounding structures of the joint, such as the bone and synovial membrane, that have sensory neurons4 and transmit stimuli to the central nervous system. With this in mind, it is plausible that by halting cartilage degradation early enough, the surrounding areas of the joint may be protected from painful stimuli, thus reducing discomfort and joint pain in patients.
Overall, there are many challenges to OA treatment. Although research is making great headway into the pathogenesis of the disease, there is still a way to go. One of the major barriers that is apparent through all the points mentioned in this review is the delay in seeking treatment. Cartilage degradation is reversible up to a point, and mechanical pain is a symptom that typically appears later in disease progression. If OA were detected earlier, there may be better chances of halting the cycle and improving quality of life. To do this, there needs to be more research into potential OA disease biomarkers and a screening process for elderly populations. With the increasing life expectancy in many developed countries, a screening set-up may be costly initially, but the benefits of implementing early treatment could far outweigh the increasing socio-economic burden that OA poses.
- Hunter D J, Bierma-Zeinstra S. Osteoarthritis. The Lancet. 2019; 393 (10182): 1745-1759. https://doi.org/10.1016/S0140-673(19)30417-9
- Heinegard D, Saxne T. The role of the cartilage matrix in osteoarthritis. Nature Reviews Rheumatology. 2011; 7: 50-56. doi:10.1038/nrrheum.2010.198
- Glyn-Jones S, Palmer A, Agricola R, Price A, Vincent T, Weinans H, Carr A. Osteoarthritis. The Lancet. 2015; 386 (9991): 376-387. http://dx.doi.org/10.1016/S0140-6736(14)60802-3
- Latourte A, Kloppenburg M, Richette P, Emerging phermaceutical therapies for osteoarthritis. Nature Reviews Rheumatology. 2020; 16: 673–688. https://doi.org/10.1038/s41584-020-00518-6
- Jiang L, Lin J, Zhao S, Wu J, Jin Y, Yu L, et al. ADAMTS5 in OA : Biological, Functions, Regulatory Network, and Potential Targeting Therapies. Frontiers in Molecular Biosciences. 2021; 8: 703110. doi: 10.3389/fmolb.2021.703110
- Troeberg L, Nagase H. Proteases involved in cartilage matrix degradation in osteoarthritis. Biochim Biophys Acta. 2012; 1824 (1): 133-145. doi:10.1016/j.bbapap.2011.06.020
- Santamaria, S. ADAMTS-5: A difficult teenager turning 20. International Journal of Experimental Pathology. 2020; 101: 4 – 20. 10.1111/iep.12344
- Burrage P, Mix K, Brinckerhoff C. Matrix Metalloproteinases: Role in Arthritis. Frontiers in Bioscience. 2006; 11: 529-543. doi:10.2741/1817
- McClurg O, Tinson R, Troeburg L. Targeting cartilage degradation in Osteoarthritis. Pharmaceuticals. 2021; 14 (2): 126. https://doi.org/10.3390/ph14020126
- Siebuhr A, Werkmann D, Bay-Jensen A, Thudium C, Karsdal M, Serruys B, et al. The Anti-ADAMTS-5 Nanobody M6495 Protects Cartilage Degradation Ex Vivo. International Journal of Molecular Sciences. 2020; 21 (17): 5992. doi:10.3390/ijms21175992
- Malemud C. Inhibition of MMPs and ADAM/ADAMTS. Biochem Pharmacol. 2019; 165:33-40. doi:10.1016/j.bcp.2019.02.033
- Santamaria S, Cuffaro D, Nuti E, Ciccone L, Tuccinardi T, Liva F, et al. Exosite inhibition of ADAMTS-5 by a glycoconjugated arylsulfonamide. Nature Research; Scientific Reports. 2021; 11: 949. https://doi.org/10.1038/s41598-020-80294-1
- Santamaria S, Yamamoto K, Botkjaer K, Tape C, Dyson M, McCafferty J, et al. Antibody-based exosite inhibitors of ADAMTS-5 (aggrecanase-2). Biochem Journal. 2015; 471 (Pt 3): 391-401. doi:10.1042/BJ20150758
- Clement-Lacroix P, Little C, Smith M, Cottereaux C, Merciris D, Meurisse S, et al. Pharmacological characterization of GLPG1972/S201086, a potent and selective small molecule inhibitor of ADAMTS-5. Osteoarthritis and Cartilage. [In press] 2021. https://doi.org/10.1016/j.joca.2021.08.012
- Latoute A, Richette P. Inhibition of ADAMTS-5: the right target for osteoarthritis? Osteoarthritis and Cartilage. https:// doi.org/10.1016/j.joca.2021.09.012
- Miller R, Tran P, Ishihara S, Larkin J, Malfait A, Therapeutic effects of an anti-ADAMTS-5 antibody on joint damage and mechanical allodynia in a murine model of osteoarthritis. Osteoarthritis and Cartilage. 2016; 24(2): 299-306. http://dx.doi.org/10.1016/j.joca.2015.09.005