Toward Wiping Out Osteoarthritis in China: Research Highlights
Osteoarthritis (OA) is currently considered more than a degenerative disorder of weight-bearing joints. Instead, it is recognized as a systemic disease affecting all joints due to causes such as aging, injury, inflammation, and metabolic disorders. The prevalence of OA is high, with 9.6% in men and 18.0% in women aged over 60 years. Most health professionals consider OA incurable, focusing exclusively on palliative treatment due to the lack of effective disease-modifying osteoarthritis drugs (DMOADs). However, recent research in China suggests that precise treatment of OA may be possible through intensive research and drug development.
Current Status of OA Research in China
Over the past four years, 3009 papers on OA from China have appeared in PubMed, bringing the total to 5359 by the end of 2019. This is more than double the number of papers published by the end of 2015, which totaled 2350. These papers cover a wide range of topics, including the mechanisms of aging, inflammation, catabolism, joint degeneration, cell survival or death, synovial fibrosis, stemness and regeneration, and immunity. They also explore risk factors such as age, obesity, metabolic syndrome, ethnicity, gender, injury, joint stress, and bone deformities. Other papers have focused on epidemiological surveys, sports medicine, traditional Chinese medicine, rehabilitation, and drug safety.
A precision medicine (PM) initiative has been launched in China to examine patient cohorts, although a high-quality patient cohort and biobank are still lacking. To address this, a multi-omics systems-based approach to PM has begun to build a patient cohort from early to advanced-stage OA of the knee, hip, and spine. A new biobank is also being developed to collect fluids, tissues, and cryopreserved cells.
Progress in Understanding the Endogenous Mechanisms of OA
Significant progress has been made in understanding the endogenous mechanisms of OA. Many OA pathogenesis genes have been discovered, and their inhibitors have been identified. These include genes encoding pro-inflammatory factors like tumor necrosis factor-alpha and interleukin-1, which are targeted by anti-inflammatory drugs such as dexamethasone and celecoxib. Other targets include genes related to aging and development, autophagy, and protein synthesis regulation, such as those encoding the mammalian target of rapamycin (mTOR) complex 1 (mTORC1). mTORC1 functions as a master regulator in autophagy, a mechanism for which Dr. Yoshinori Ohsumi was awarded the 2016 Nobel Prize in Physiology or Medicine. Additional targets include matrix metalloproteinase, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), growth factors, Cathepsin-k, the Wnt/beta-catenin pathway, vascular endothelial growth factor, inhibitor of nuclear factor kappa-B kinase (IKK), nitric oxide (NO), and genes crucial for subchondral bone development such as estrogen receptors and cyclooxygenase (COX)-2. Despite these discoveries, effective DMOADs are still lacking.
Promising Therapeutic DMOADs
Several promising therapeutic DMOADs are under investigation. Wnt inhibitors specifically targeting the canonical Wnt pathway show potential, including SM04690, a small-molecule inhibitor of the Wnt pathway for treating moderate to severe knee OA. SM04690 appears safe and has a positive effect on joint pain and function. Another promising candidate is Sprifermin, a recombinant human fibroblast growth factor 18. A double-blind, randomized placebo-controlled trial involving intra-articular administration of 100 mg Sprifermin every 6 or 12 months in patients with severe knee OA revealed no serious safety concerns and improved total femorotibial joint cartilage thickness after 2 years.
Platforms for OA Drug Screening
Translating promising drug candidates into clinical success often fails. The ideal drug needs to stop pain and joint destruction by preventing cartilage cell death and synovitis while protecting bones, with minimal or no side effects. However, DMOAD development has been hampered by a lack of experimental models that replicate OA disease status. Animal models face challenges such as funding support, time constraints, ethical concerns, and debate over whether animal studies mirror human effects. A new cartilage-on-a-chip (COAC) platform may allow high-throughput drug screening for OA. This platform generates a microfluidic cartilaginous micro-construct in a 3D microenvironment by culturing adult human articular chondrocytes in a synthetic polyethylene glycol hydrogel with an adequate culture medium contact surface. The resulting COAC is rich in type II collagen and aggrecan and can mimic OA traits through mechanical cyclical rounds of hydrogel confinement, compression, and stimulation at the genetic and cellular levels without cytokines. This represents a paradigm shift for in vitro models and is more effective than ex vivo and in vitro models with pro-inflammatory cytokines. The effects of anakinra, rapamycin, and celecoxib have been demonstrated on COACs. For drug screening purposes, COAC needs to develop into a high-throughput system with increased model complexity and new tissue-tissue interfaces to create a “joint on a chip.” An integrative bioinformatics platform for rapid identification and validation of novel rheumatoid arthritis drug treatments also has potential for OA drug screening, along with the Nanning National Engineering Center of Chinese Herbal Medicine Garden.
Recent Research Highlights
In addition to the COAC method, other milestones in OA research have been reached. OA was recognized by the US Food and Drug Administration as a serious disease, as it increases the mortality rate of dysmotility patients up to double that of healthy controls. Mechanism-based drug development research has expanded from autophagy-related aging research to multi-omics-based PM, promising novel insights into OA taxonomy and potential recommendations and guidelines in China. One project is investigating rapamycin modifications to enable chondrocytes to survive longer in articular cartilage. For PM, deep phenotyping and understanding the complex pathophysiology of OA require next-generation sequencing (NGS) platforms and a team including bioinformaticians, biostatisticians, and computational biologists. The metabolomics platform, along with metabolomics bioinformaticians and artificial intelligence (AI), can be used for phenotyping, outcome prediction, and uncovering disease mechanisms. Single molecule array technology allows ultrasensitive and precise detection of protein and nucleic acid biomarkers for accurate taxonomy and can be combined with the omics of imaging technology to develop stable, detectable, and quantifiable biomarkers.
Non-surgical management of OA is another promising area. Optimization of musculoskeletal health has been discussed worldwide and in China, with acupuncture and Tai Chi now included in the Osteoarthritis Research Society International (OARSI) guidelines for managing knee OA. The “Good Life with Osteoarthritis in Denmark” (GLAD) program was introduced to China for people with hip or knee OA, resulting in reduced pain and improvement in daily activity and quality of life. The GLAD program involves two education sessions and 12 tailored neuromuscular exercise sessions.
Updates of OA clinical trials, classification, taxonomy, and clinical guidelines are needed in China. Several OA multicenter clinical trials are investigating traditional Chinese medicine Celastol, Qufengzhitong capsule, and more. OA classifications and updated OA guidelines for China have also been drafted by an expert panel, with papers on these topics in preparation.
Our Focus for the Future
Several topics need to be addressed to treat OA precisely. Aging is generally the most important OA risk factor, related to mechanisms such as soma-germline distinction, epigenetics, autophagy, reactive oxygen species, and vitamin D receptors. Targeting these systems to delay aging may be meaningful for preventing OA. Injury prevention, reducing obesity, and changes in the microbiome may also help treat OA precisely. Regarding aging turning points, the degenerative OA process roughly begins at 30 to 34 years old. Biomarkers or magnetic resonance imaging (MRI) can detect OA genesis as changes in the composition of bone, cartilage, and soft tissues at 35 to 50 years old. Later, MRI scans can reveal structural changes in the bone, cartilage, and other soft tissues at 51 to 60 years, followed by X-ray detection of structural changes in bone (i.e., joint failure) at 61 to 70 years. End-stage disease (i.e., joint death) generally occurs at 71 to 78 years old, often requiring total knee/hip arthroplasty (TKA/THA) or total knee replacement (TKR)/hip and knee replacement (HKR). The aging process might be delayed to prevent OA, which is a major focus of mTOR and autophagy research. The reversible turning point could be detected via high-dimension multi-omics data. One gap remaining in OA research is understanding how cartilage degenerates and when this process starts. If we can detect degeneration during the early phases of OA, could we stop or delay it?
Issues in China
The Chinese government may provide more funding for OA researchers along with the “Healthy China 2030” initiative. Last year, a guideline for the national key R&D program for OA, osteoporosis, and bone fracture was written to accelerate Chinese OA research. However, for Chinese translational research to be fully effective, we need mental and cultural change to create an environment of copyright and patent protection. We also need to move toward more national and international collaboration and develop new open and fair systems to evaluate translational researchers and institutions against superficial achievements, focusing instead on innovation, originality, and impact to develop the career path of OA researchers in hospitals. We need to tighten the relationships between academia and the industry and create new training programs for translational researchers and/or ambitious youth, OA research proposal layman-targeted versions, OA research foundations alongside donations to foster frontiers, OA patient-engaged symposiums, as well as creating biobank systems.
It usually takes 15 years for evidence from reviews, papers, and textbooks to be implemented into clinical practice. However, the Chinese government may improve the efficacy of OA translational medicine by integrating healthcare, academia, and the industry through its unique powerful executive system. Moreover, Shenzhen has been recently approved as the pilot demonstration area of socialism with Chinese characteristics embracing innovation. Local companies such as Tencent Inc. and BGI-Shenzhen indeed have strength in bioinformatics, machine learning, and artificial intelligence. This may provide novel analytics and computational approaches to link imaging with OA tissue and joint mal-function. Consequently, they might help realize the precision medicine of combining clinical and imaging parameters for DMOAD trials.
In conclusion, although tremendous progress has been made toward treating OA precisely, further effort is needed, including developing high-throughput platforms for DMOAD screening, which will help us reach our goal.
doi.org/10.1097/CM9.0000000000000746
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