How do circadian clocks in chondrocytes contribute to cartilage function in health and disease
Lead Research Organisation:
University of Manchester
Department Name: School of Biological Sciences
Abstract
This research focuses on the molecular/cellular mechanisms of biological clocks in the joint cartilage and their contributions to the development and severity of damage in osteoarthritis (OA). Circadian (about a day) clocks are endogenous time pieces in our bodies that are responsible for generating 24 hour rhythms in behaviour and physiology. Disruptions of circadian rhythms by advanced age, shift work or jet lag can have severe impacts on body functions and disease risks. By culturing chondrocyte cells (the only cell type in cartilage) in petri dishes, isolating cartilage pieces, and a surgical operation which mimics OA in clock disrupted mouse knee joint, we expect to unravel: 1) Which rhythmic genes in cartilage rely on the local chondrocyte clock to maintain their circadian pattern of expression? 2) Can we target cartilage circadian clock proteins as a novel approach to alter chondrocyte gene expression? 3) Do alterations in specific components of the clock mechanism cause early onset OA, or leave mice more susceptible to surgical injury-induced OA? This project will generate new data and knowledge that will benefit researchers working on circadian biology, chondrocyte biology, ageing and joint diseases. It is also likely to benefit pharmaceutical industries who are interested in developing new approaches to targeting arthritic diseases. Outcomes will advance our understanding of the role circadian rhythms play in the healthy state of the joint cartilage, so will also be of value to the general public.
Technical Summary
Circadian clocks drive ~24 hour rhythms in nearly all aspects of mammalian physiology and behaviour. Changes of circadian rhythms during ageing are now thought to underpin many of the age-associated pathologies. Our preliminary data demonstrates cell autonomous circadian clocks in the mouse cartilage tissue and human chondrocytes. Importantly, our cartilage circadian transcriptome profiling data strongly implicate circadian clocks as regulators of key genes involved in cartilage homeostasis, in chondrocyte survival and with potential importance in osteoarthritis (OA) pathogenesis. In this proposal, we will combine a novel transgenic mouse model with chondrocyte-specific ablation of circadian clock, with an experimental mouse OA model and with supporting human chondrocyte experiments to address the following key questions: 1) Which rhythmic genes in cartilage rely on the local chondrocyte clock to maintain their circadian pattern of expression? 2) Can we target cartilage circadian clock proteins as a novel approach to alter chondrocyte gene expression? 3) Do alterations in specific components of the clock mechanism cause early onset OA, or leave mice more susceptible to surgical injury-induced OA? These studies may identify novel strategies that target clock components or circadian rhythm to restore cartilage tissue homeostasis and prevent/delay arthritic disease onset. Such knowledge may also improve current treatments for joint diseases, for instance, by timing drug delivery to increase efficacy and reduce toxicity.
Planned Impact
Osteoarthritis (OA) is the most prevalent age-related joint disease, causing pain and stiffness in joints and affecting at least 8 million people in the UK. There is currently no cure for this condition, and at later stages of OA, joint replacement becomes the viable option. The significant disability associated with OA impairs the quality of life, making OA a serious medical concern and economic burden. The greying of the population and the ever-increasing demands of our modern 24/7 society frequently lead to disruptions of circadian rhythms generated by our body clocks, which consequently increase risks of developing various diseases, including obesity, diabetes and cardiovascular diseases. This project will combine studies in a novel transgenic mouse model with chondrocyte-specific clock disruption, human chondrocytes in culture, and an experimental model of OA, in order to gain significant biological insights into the function of cartilage clocks in tissue homeostasis and disease susceptibility. Our research may identify novel therapeutic strategies for joint diseases, or improve the efficacy of current treatments, therefore has an enormous potential for improving health and quality of life. Moreover, the functional significance of circadian rhythms in OA will emphasize the importance of maintaining robust circadian rhythms through healthy life styles, which will have a long lasting impact on the health and well being of the ageing population.
Who will benefit from this research?
This project will initially benefit a wide range of researchers, as described in the Academic Beneficiaries section. The pathways identified by this project that link circadian clocks to chondrocyte biology(such as REV-ERBa and RORa which belong to the nuclear hormone receptors super family) are likely to also benefit pharmaceutical industries. In fact, GSK and Pfizer have already started investigating the possibilities of targeting NHRs (PPARa/g and LXR) for arthritic diseases. Further mechanistic insights into how the clock related NHRs regulate chondrocyte pathways will greatly help refine the drug targets and design principles in this regard. Moreover, our studies indicate that many of the genes involved in cartilage homeostasis, in chondrocyte survival and with potential importance in OA pathogenesis are rhythmically expressed, including matrix-degrading enzymes, catabolic/anabolic signalling molecules, and one of the OA susceptibility genes (GNL3) newly identified by the arcOGEN GWAS study. The rhythmic nature of these targets call for novel treatment strategies for joint diseases, which take into accounts the time-of-day effect, i.e., chronopharmacology or chronotherapy. On the other hand, the quest for prognostic biomarkers of joint diseases also has to consider their potential daily variations. Finally, elucidating the roles of circadian rhythms in cartilage physiology and OA susceptibility will have profound impacts on public understanding of rhythm disruptions and disease risks. We expect that the outcomes will be media worthy and be of interest to the OA sufferers, health care professionals working with OA patients, the general public and the elderly population.
How will they benefit from this research?
Outcomes from this research will be published expeditiously in high-profile journals that have open access options. Results will also be disseminated by participating in conferences, seminars, public lectures and media reports. Key findings will also be featured on the PI and Co-PI's group web pages. In the long term, it may be possible to translate the outcomes into novel medical practice that aims at ameliorating arthritic diseases, e.g., by targeting circadian rhythms/clock components, or timed delivery of current therapeutic medications. As such, this project holds the potential of a profound long-term impact on health and quality of life, with a long lasting economic and social impact.
Who will benefit from this research?
This project will initially benefit a wide range of researchers, as described in the Academic Beneficiaries section. The pathways identified by this project that link circadian clocks to chondrocyte biology(such as REV-ERBa and RORa which belong to the nuclear hormone receptors super family) are likely to also benefit pharmaceutical industries. In fact, GSK and Pfizer have already started investigating the possibilities of targeting NHRs (PPARa/g and LXR) for arthritic diseases. Further mechanistic insights into how the clock related NHRs regulate chondrocyte pathways will greatly help refine the drug targets and design principles in this regard. Moreover, our studies indicate that many of the genes involved in cartilage homeostasis, in chondrocyte survival and with potential importance in OA pathogenesis are rhythmically expressed, including matrix-degrading enzymes, catabolic/anabolic signalling molecules, and one of the OA susceptibility genes (GNL3) newly identified by the arcOGEN GWAS study. The rhythmic nature of these targets call for novel treatment strategies for joint diseases, which take into accounts the time-of-day effect, i.e., chronopharmacology or chronotherapy. On the other hand, the quest for prognostic biomarkers of joint diseases also has to consider their potential daily variations. Finally, elucidating the roles of circadian rhythms in cartilage physiology and OA susceptibility will have profound impacts on public understanding of rhythm disruptions and disease risks. We expect that the outcomes will be media worthy and be of interest to the OA sufferers, health care professionals working with OA patients, the general public and the elderly population.
How will they benefit from this research?
Outcomes from this research will be published expeditiously in high-profile journals that have open access options. Results will also be disseminated by participating in conferences, seminars, public lectures and media reports. Key findings will also be featured on the PI and Co-PI's group web pages. In the long term, it may be possible to translate the outcomes into novel medical practice that aims at ameliorating arthritic diseases, e.g., by targeting circadian rhythms/clock components, or timed delivery of current therapeutic medications. As such, this project holds the potential of a profound long-term impact on health and quality of life, with a long lasting economic and social impact.
Publications
Berenbaum F
(2016)
The brain-joint axis in osteoarthritis: nerves, circadian clocks and beyond.
in Nature reviews. Rheumatology
Dudek M
(2017)
The intervertebral disc contains intrinsic circadian clocks that are regulated by age and cytokines and linked to degeneration.
in Annals of the rheumatic diseases
Dudek M
(2014)
Running on time: the role of circadian clocks in the musculoskeletal system.
in The Biochemical journal
Dudek M
(2023)
The clock transcription factor BMAL1 is a key regulator of extracellular matrix homeostasis and cell fate in the intervertebral disc.
in Matrix biology : journal of the International Society for Matrix Biology
Dudek M
(2021)
Circadian time series proteomics reveals daily dynamics in cartilage physiology.
in Osteoarthritis and cartilage
Dudek M
(2016)
The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity.
in The Journal of clinical investigation
Dudek M
(2023)
Mechanical loading and hyperosmolarity as a daily resetting cue for skeletal circadian clocks.
in Nature communications
Gonçalves C
(2024)
Modulation of circadian rhythms in articular cartilage by heat pulses
Gonçalves C
(2019)
Timing metabolism in cartilage and bone: links between circadian clocks and tissue homeostasis
in Journal of Endocrinology
Title | One of our research images was chosen as the cover image of Nature Reviews Rheumatology 2018 (all 12 issues) |
Description | An experimental image of degenerative articular cartilage in the clockless mouse model was chosen as the cover image of Nature Reviews Rheumatology 2018 (all 12 issues) |
Type Of Art | Image |
Year Produced | 2018 |
Impact | All readers of the NRR journal will be able to see this image and the research story associated with it. |
URL | http://www.nature.com/nrrheum/journal/v14/n2/covers/index.html |
Title | https://www.asmb.net/image-contest-winners |
Description | In 2019, Honor Morris' research image was one of the winners of the ASMB (American Society for Matrix Biology) image contest. |
Type Of Art | Image |
Year Produced | 2019 |
Impact | The image showcases our cutting edge techniques in imaging collagen matrix. |
URL | https://www.asmb.net/image-contest-winners |
Description | Arthritis Research UK Senior Research Fellowship |
Amount | £845,918 (GBP) |
Organisation | Versus Arthritis |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 08/2015 |
End | 08/2020 |
Description | Biomedical Research Consortia Award |
Amount | £66,000 (GBP) |
Funding ID | 097820/Z11/B |
Organisation | Wellcome Trust |
Department | Wellcome Trust Institutional Strategic Support Fund |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2014 |
End | 04/2016 |
Description | MRC DTP PhD studentship |
Amount | £100,011 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 08/2017 |
End | 08/2021 |
Description | MRC DTP studentship |
Amount | £98,000 (GBP) |
Organisation | MRC Doctoral Training Program |
Sector | Academic/University |
Country | United Kingdom |
Start | 09/2021 |
End | 09/2025 |
Description | MRC project grant |
Amount | £546,000 (GBP) |
Funding ID | MR/T016744/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 01/2020 |
End | 12/2022 |
Description | Project grant |
Amount | £459,661 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 01/2017 |
End | 12/2020 |
Description | Clock genes, human ES cells and chondrogenesis |
Organisation | University of Manchester |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | I provide insights/expertise on circadian clock genes. |
Collaborator Contribution | Prof. Kimber provide expertise on hES differentiation. |
Impact | We have jointly recruited a full time PDRA to work on this project. We have a joint PhD studentship being advertised. |
Start Year | 2013 |
Description | Clocks in musculoskeletal system |
Organisation | University of Hong Kong |
Country | Hong Kong |
Sector | Academic/University |
PI Contribution | My lab has started working with Prof. Danny Chan (Hong Kong University) on circadian rhythms in the musculoskeletal system. |
Collaborator Contribution | The Chan lab has strong expertise in cartilage/intervertebral disc biology, development and genetics. We have started by exchange of visiting scientists. |
Impact | New collaboration. |
Start Year | 2018 |
Description | Glucocorticoid rhythm, osteoarthritis and bone loss |
Organisation | University of Sydney |
Country | Australia |
Sector | Academic/University |
PI Contribution | I am a co-I on a successful NHMRC research grant led by Prof. Hong Zhou of Sydney University. The total grant value is Australian dollars 850, 602. Duration is 48 months. |
Collaborator Contribution | We will collaboration of the role of glucocorticoid rhythms in osteoarthritis and bone loss. |
Impact | One successful grant from NHMRC. |
Start Year | 2023 |
Description | Mechanical loading and chondrogenesis |
Organisation | AO Foundation |
Department | AO Research Institute |
Country | Switzerland |
Sector | Charity/Non Profit |
PI Contribution | I bring expertise in circadian biology to chondrogenesis models. |
Collaborator Contribution | Prof. Martin Stoddart has expertise on mechanical loading of stem cells towards chondrogenesis for tissue repair. |
Impact | Prof. Stoddart has secured a AO Foundation grant of CHF 535, 305. Duration 36 months. I am a Co-I on the grant. |
Start Year | 2023 |
Description | Smart cells chondrocytes |
Organisation | Washington University in St Louis |
Country | United States |
Sector | Academic/University |
PI Contribution | We have a joint publication currently under review at Science Advances. |
Collaborator Contribution | The Guilak lab generated smart cells chondrocytes which can produce anti-inflammatory agents upon inflammation. |
Impact | Multi-disciplinary collaboration as it spans genetic engineering, immunology and circadian biology. |
Start Year | 2020 |
Description | UK Biobank analysis of shift workers and osteoarthritis risk |
Organisation | University of Bristol |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | A new collaboration is started with Dr. Ben Faber, University of Bristol on UK BioBank analysis for associations between shift work and risks of osteoarthritis |
Collaborator Contribution | The Faber group has expertise to analyse UK Biobank data. |
Impact | OARSI abstract was submitted to the conference in 2024 |
Start Year | 2023 |
Description | circadian rhythms, BMP signaling and tendinopathies |
Organisation | University of Manchester |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | I provide the circadian clock expertise, tg mouse models and clock reporter cells to the project. |
Collaborator Contribution | Karl provided tendon analysis expertise, EM and osteogenic differentiation to the project. |
Impact | We have a joint publication which will be submitted within a few weeks. We also have a joint PhD project which is being advertised. |
Start Year | 2012 |
Description | A press release on the importance of consistent exercise timing for skeletal health |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | https://www.manchester.ac.uk/discover/news/exercise-at-consistent-times-could-help-re-align-your-body-clocks-for-better-skeletal-health-and-performance-scientists-suggest/#:~:text=Consistent%20daily%20patterns%20of%20exercise,of%20Manchester%20scientists%20has%20argued. This press release followed a paper we published in Nature Communications. This was picked up by many media outlets, including the Mirror: https://www.mirror.co.uk/lifestyle/health/exercising-right-time-each-day-31879016 |
Year(s) Of Engagement Activity | 2023 |
URL | https://www.mirror.co.uk/lifestyle/health/exercising-right-time-each-day-31879016 |
Description | BBC Breakfast |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | I was interviewed by BBC Breakfast to discuss my body clock research and its implications in chronotherapy and shift work |
Year(s) Of Engagement Activity | 2018 |
Description | BBC Breakfast |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | I was invited to BBC Breakfast to comment on a BBC Documentary on Body Clocks |
Year(s) Of Engagement Activity | 2018 |
Description | BBC Radio interview |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Our work on clocks and osteoarthritis has received 30+ media coverages, including a BBC Radio interview. My research has reached an audience far beyond the immediate scientific peers. |
Year(s) Of Engagement Activity | 2007,2013 |
Description | Press release and radio interview |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | My ARUK Fellowship Award and the related research story in J Clin Invest have been covered by a press release and BBC Radio interview. |
Year(s) Of Engagement Activity | 2016 |
Description | Public lecture to a local school |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | I delivered a public lecture to the senior year students of the Withington Girls School on "Understanding your body clocks", which inspired students to pursue a scientific career. |
Year(s) Of Engagement Activity | 2016 |
Description | Public talk at Withington Girls School |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | 30 pupils attended my talk, which inspired them to engage in science for their future career. Students became very interested in biological clocks and sleep, and would like to pursue a relevant degree programme in future. |
Year(s) Of Engagement Activity | 2013 |