Milestone study uncovers genetic risk factors for spine osteoarthritis

Reviewed by Emily Henderson, B.Sc.Nov 8 2021

Scientists from the LKS Faculty of Medicine, The University of Hong Kong (HKUMed), contributing as part of the 'Genetics of Osteoarthritis (GO)' consortium to the world's largest study of over 800,000 individuals, have identified genetic risk factors - variants associated with SOX5 and CHST3 genes, key regulators of the development of the intervertebral discs, to be implicated in spine osteoarthritis (OA). The findings are now published inCELL, a premier scientific journal.

OA is the degeneration of joints, and a major cause of pain and disability in older people. There is no cure for OA because the causes are complex and the mechanisms are unclear. Therefore, identifying the risk factors for the disease is crucial and urgent to guide the development of novel treatments that will benefit patients.

Research methods and findings

Osteoarthritis affects multiple joints such as the knee, hip, hand and spine. This milestone study has analysed 826,690 individuals from nine populations, including Hong Kong Chinese from Southern China, Japanese and European, and discovered 100 genetic risk variants for OA, of which 52 were new; and identified novel drug targets.

The HKUMed team helped identify the SOX5 gene, which is known to be essential for the development of the intervertebral discs, to be implicated in spine OA. The study also showed that spine OA was genetically correlated to OA at other joints including hip, knee, finger and thumb. Interestingly, it was also found that the CHST3 gene was among the top three genes most confidently linked to hip OA. CHST3 was previously found by the Hong Kong team to be associated with intervertebral disc degeneration which causes back pain.

'This study demonstrates the power of genetics to uncover biological mechanisms and identify new treatment targets for complex human diseases, when researchers are willing to share data collected from different countries,' remarked Professor Sham Pak-chung, Suen Chi-Sun Professor of Clinical Science, Research and Training Lead of the Centre for PanorOmic Sciences and Chair Professor of Psychiatric Genomics, Department of Psychiatry, HKUMed; Co-Director of The State Key Laboratory of Brain and Cognitive Sciences, HKU, who led the spine OA genetic analyses.

These findings suggest a strong link between degeneration of the intervertebral discs, OA and back pain. Furthermore, spine OA was genetically correlated not only with back pain, but also knee, hip and neck/shoulder pain. The study also showed that body weight rather than fat mass was genetically correlated with OA, and that weight-bearing and non-weight-bearing joints differed in genetic influences.

The putative OA genes identified in the study have diverse biological functions, including key molecules in the formation and development of the skeleton, and pathways that control how cells respond to stress. These biological processes are modifiable and represent potential treatment targets. Encouragingly, the study showed that some of the putative OA genes could be targeted by existing drugs or small molecules.

OA has such a debilitating impact on our daily life. Based on our results, I am sure that a treatment can be developed to relieve some of the back pain arising from OA, that will have enormous impact on millions of people."

Professor Kathryn Cheah Song Eng, Jimmy and Emily Tang Professor in Molecular Genetics, Chair Professor of Biochemistry, School of Biomedical Sciences, HKUMed and coordinator of the study

'The association of spine degeneration with hip and knee joint degeneration is of particular significance, implying that treatments that help the hip and knee joint may be useful for the spine and vice versa. It opens up the field to kinds of possibilities to the benefit of both groups of patients,' commented Professor Kenneth Cheung Man-chee, Jessie Ho Professor in Spine Surgery, Chair Professor and Head of Department of Orthopedics and Traumatology, HKUMed, who pioneered the establishment of the Hong Kong Degenerative Disc Disease Population Cohort Study.

'OA is a complex disease involving many factors. This collaborative effort illustrates the benefit and power of international sharing of large-scale data from cohort studies, and thinking outside the box in extracting additional information so that far reaching goals can be achieved for the development of treatments that will benefit patients,' remarked Professor Danny Chan, S Y and H Y Cheng Professor in Stem Cell Biology and Regenerative Medicine, Interim Director of the School of Biomedical Sciences and Assistant Dean (Research Postgraduate Studies), HKUMed, who is an expert in the development of joints and intervertebral disc degeneration and also helped establish the Hong Kong cohort.

Significance of the study

To date, no genetic factor for spine OA has been identified. The study represents a major advance, and paves the way for further research to find new and more effective treatments for sufferers. Since SOX5 is a master regulator of many genes, this study provides the foundation for the identification of downstream genetic factors that impact the development of spine OA. The genes identified for OA of other joints that are validated as therapeutic targets may also be relevant to spine OA as well as intervertebral disc degeneration. The ideas for translation that exploit knowledge of genetic risk factors into potential drugs for OA, which, if effective, could significantly improve the quality of life of patients suffering from osteoarthritis.

'Patients suffering from back pain constitute a substantial portion of musculoskeletal disorders. Of the two major causes, disc degeneration and OA, the former can be identified by MRI, whereas OA is difficult to pinpoint. Thus, only symptomatic treatment is possible by using anti-inflammatory drugs, and various modalities of physiotherapy. The clarification of the genes responsible for OA spine is a major step forward towards the possibility of more specific treatment, such as new drugs,' said Professor John Leong Chi-yan, Emeritus Professor and Honorary Professor of the Department of Orthopaedics and Traumatology, HKUMed; former Chairman of the Hospital Authority.

'This is a major step forward in understanding this debilitating disease and could not have been achieved without this international team effort,' said Professor Eleftheria Zeggini, leader of the GO Consortium and Director of the Institute of Translational Genomics at Helmholtz Zentrum München.