New insights into osteoarthritis onset with Prof Frank Beier

hello and welcome to this edition of joint action [Music] this podcast is dedicated to all those out there who have osteoarthritis on the show we unpack the truth and demystify the myths about the disease and its management if you have joint pain and want to know more about how to manage it from the world's best experts you've come to the right place without further ado it is time to welcome your host david hunter hello and welcome to this edition of the joint action podcast where we're discussing new insights into osteoarthritis onset i'm regularly asked by

both patients health professionals and colleagues what new developments are happening in this space that might provide pivotal changes to therapies at this point in time there is lots of improvement that can be made to improve our therapeutic armamentarium pain is still a huge unmet need as far as therapeutic targets is concerned so there's lots of improvement that can be made and despite the large prevalence of osteoarthritis there is no clinically approved drug which provides a cure currently most drugs focus on relieving symptoms such as pain experiments in the lab however have provided insight on osteoarthritis

onset and progression and will likely guide therapeutic development we know that osteoarthritis is a disease of the whole organ meaning that any of the tissues involved in the synovial joint can be affected the interplay between various cell types involved is complex and understanding the interactions between cartilage bone synovium and other tissues in the joint might be critical to therapeutic development skeletal development likely plays a very important role in predisposition to disease through the identification of serious pathologies such as various forms of dwarfism what in medical terms are called chondrodysplasias the role of transcription factors and

epigenetics is increasing our understanding of disease genesis the study of epigenetics in osteoarthritis the mechanism by which the human genome alters its gene expression without changing the primary dna sequence has provided valuable information on novel risk factors for the disease and these are potential therapeutic targets for osteoarthritis dr frank baier joins us on the show today entitled new insights into osteoarthritis onset and the focus of the discussion today will be on recent advances in osteoarthritis understanding with a particular emphasis on novel targets and epigenetics frank baier is the canada research chair in muscular skills research

at the university of western ontario and a member of western's bone joint institute he is a professor and chair of the department of physiology and pharmacology and his lab explores mechanisms controlling cartilage and joint biology using genetically engineered mice in combination with surgical dietary and activity manipulations this is the natural fit with the objectives of the bone joint institute an environment that's helped to foster collaborations with fellow researchers from other fields such as clinicians and imaging scientists as an engaged member of the institute's operations committee dr bias sees value in the institute's priorities that improve

his training program and that support the acquisition of additional research funds he's published over 100 peer-reviewed articles and has given over 100 invited presentations and his work is supported by the canadian institute of health research and the arthritis society he was a member of the board of directors of the osteoarthritis research society international and several editorial boards including being deputy editor for osteos rising college frank it's great to see you and thank you so much for joining us today on the show thank you for having me in the first part of the show i usually

just try to get to know the person i'm speaking to a little bit better both for myself and the listeners who are out there but can you share with the listeners a little bit more about your background and what your typical day looks like okay absolutely so i grew up in germany did my phd there and then i moved to canada first for post-op in calgary and then to my current position in london in ontario i used to work mostly in developmental biology studying how the skeleton forms and growth in the first place but then

gradually transitioned into our current work on osteoarthritis and as we might talk about later those two areas the development of the skeleton and osteoarthritis are quite linked my typical day one of the nice things about this job is there is no typical day every day is different but i am a department chair so about half my time i spend on meetings organizing our teaching program yeah on all kinds of committees hr stuff and the other time the other half i try to spend on research working with my team discussing data planning experiments reading papers listening

to seminars things like this so lots of different things but every day is different yeah and i think that variety is probably what also keeps us engaged and enthused moving forward so it's so so important yeah frank when you're not doing your day job what is it that you like to do uh i like to go outside hiking walking biking that's probably uh what i like the most i also like to read i like to hang out with friends and spend time with my family yeah when when there's time well it sounds like you've got

a lovely environment to uh to get outside there as well and uh hopefully as the weather's starting to warm you get to enjoy that a little bit more yeah definitely the next one's a little more complicated but if you had to describe yourself in five words what would they be i'm very optimistic i think i'm fairly laid back almost australian i passionate about issues like environment social issues health of course i'm probably not the most organized person and they're not detail-oriented person and i think that's been more than five-thirds a lot more so i think

everybody has a perception that everybody in australia is very uh laid-back i think we're um very reflective and calm but despite i think a lot of perceptions out there i think most of us are pretty intense when it comes down to it but i'm really interested in the the social issues part are there particular social issues at the moment that are getting you more engaged than not well i think i've always been quite passionate about about anti-racism of course in north america and the black racism and the indigenous racism is big women's right but i

think what i'm also getting more and more attuned to is social disparities and how they for example affect health growing up poor with pure education with lower quality food how social disparity affects health for example but then of course all these issues are related yeah well i think these issues are really very pressing at the moment i think particularly given the inequities that we have in our society but i think as a as a group of scientists that are also involved in a disease where these inequities whether they be around race gender but also socioeconomic

inequality and some of the barriers that people from different parts of society have at accessing health care and getting healthy alternatives that's so so important to our disease as well so it's good to see good to see you thinking about it now the topic of the day is really to try to get a better handle on new insights into osteoarthritis particularly as it relates to potential therapeutic opportunities and what i might start by doing frank is if it's okay just tell us a little bit about what the focus of your lab is and then we'll

dive into those topics a little bit further yeah so the the focus the main focus of my lab is really understanding molecular mechanisms that drive osteoarthritis and in particular i think we're focused on early stages of osteoporosis what starts it and drives these first stages so we use animal models to identify new molecular changes and then we target for example specific genes that we think are important we manipulate those genes in mice and see does osterdrite is still developed the same way or less or more that's basically the main focus of my lab looking at

all kinds of different molecules yeah and you know i guess just extending that a little bit further one of our great friends and your good friends chris little has told me that you know he's cured osteoarthritis hundreds of times in different species of mouse presumably you've had a similar experience and see similar optimism coming from the animal field yeah we created many mutant wise that for example don't respond with osteoarthritis when we do knee surgery so yeah we cured it many times and that shows both our strengths but even more so the weakness of these

animal models i think they are important to understand mechanisms but we we got to do much better job in making them relevant using white ages white numbers right sex and so on yeah and that's potentially a topic for another day but i think the yeah the translation from the lab to the human insights and practical applications is not necessarily happening as well as it might at the moment but irrespective of that what have we learned that's i guess pivotal and critical from mouse models of osteoarthritis and how does this affect us when thinking about the

human condition i think we learned lots lots of details of course of specific pathways but i think two two main things is maybe one is how development is linked to osteoarthritis how we develop how for example the shape of our joints when they develop how how they then affect our risk for osteoporosis because the shape of our joints determine the loading patterns for example the other part and that's where i think my lab spends quite a bit of time on is that of course we have molecular changes in osteoarthritis like in in all other diseases

but there's different forms of osteoarthritis where we have some genes to something in for example in osteoporosis that's induced by an injury which we mimic by surgery on the knee and then the same gene might do nothing when we just have an age-related form of osteoporosis or an obesity related form of osteoarthritis so there's different molecular pathways in different types and different forms of osteoarthritis that's something we learned from mouse studies mylab and many others yeah that's so so important so i might just dig into the shape aspect and then come back as a molecular

piece uh a little bit later but at least from the shape perspective in at least in human studies we're learning a little bit more about the contact stresses and the mechanics in the joint that play potentially an important role in the onset of osteoarthritis are there parallels that you're seeing in mice and their skeletal development that might parallel to the human condition and some of what particularly imaging findings are learning about shapes of joints i think if you look at the hip shape there are certainly parallels where there is a nice example where human studies

showed that variations in a gene called gdf5 give rise to bigger risk higher risk foster arthritis and if we model some of this and mice you see gf5 determines the hip shape and determines the risk of osteoarthritis in the hip for example that's that's probably the the most classical example of this and the parallels there for gta 5 frank are they related to shape abnormalities like femora assembler impingement or fai or dysplasia or it's hard to say at this point it's it's tough to say whether it's exactly the same because the anatomy is somewhat different

in the mice of course but the the outcomes seem to be related in terms of uh osteoarthritis forms you know yeah no that's i think important parallels and particularly for people out there who have hip osteoarthritis we know that shape abnormalities are really important in predisposing to osteoarthritis and various studies have suggested about 85 to 90 percent of a person's likelihood of developing osteoarthritis may come from abnormalities and the shape both of the proximal femur and pelvis yeah from a molecular standpoint you mentioned that there are different molecular changes that are occurring in in mice

that are older or that are obese or that are injured other any that you see is particularly promising as far as either the understanding of the onset of the disease or potentially being therapeutic targets and people that have those different types of onset i think so yeah i mean we we know by far the most about the post-traumatic models these are the injury-induced models in animals where we have for example clear inflammatory factors that might be important there and maybe less important than other forms of osteoarthritis there might be pathways like the wind pathway for

example which is a growth factor pathway really important in development of the skeleton and also the maintenance so i think there are some from our lab there's a number of nuclear receptors which are transcription factors so so gene regulator regulatory proteins that play a role in different forms of osteoarthritis and one nice thing with those proteins is that we have a lot of drugs that work on them already in the clinic for other diseases so i think there are options there that we can follow up none of is is ready for the clinic yet but

i think we have a lot of these so on on that note obviously disease modification is a passion of mine and a great interest for many in the field um and there are a number of disease modifying agents that are in late stage therapeutic development that more often than not those trials just take a whole population of people that oftentimes have later stage osteoarthritis irrespective of how they may have developed the osteoarthritis in the first place do you see better ways of stratifying populations and targeting treatments based on insights that you're getting in the laboratory

i think i mean i think that's where we have to get whether we are getting there i think mri certainly has a lot of potential to help the stratifying but it's likely not gonna be one a tool that we can use very broadly in the population but we can maybe combine it with more easy parameters biochemical parameters gate and use the research to to really correlate certain mri findings for example with other parameters that we can measure more easily to help stratify patients i think there's the obvious ratifications whether it was an injury or not

there's bmi there's some other clinical parameters but i think there's lots of potential there but it's we are not there yet but i think it's key yeah no there's a lot of room for improvement in our understanding and the application of those even simple stratification methods as you say just the history of injury or the person who's above a healthy weight are relatively simple to apply and might provide opportunities for more targeted therapy now another area that you've done a lot of work in is that in the role of epigenetics and osteoarthritis so in the

first instance just tell us what epigenetics are and at least from the learnings that you've had what role does this play in osteoarthritis the field of epigenetics is a relatively new field and there's different definitions of it i think i'll probably provide the most practical one as it's used basically epigenetics is a number of molecular processes that regulate which genes are on and which genes are off so for example in osteoarthritis we have certain genes that are being switched on that includes for example genes for enzymes that break down collagen and other markers so these

genes are usually not very active but in osteoarthritis the genes are being turned on and those processes that control whether the genes are on and off many of them fall under this epigenetic mechanisms there's a number of different pathways in epigenetics but in a broad pattern this is epigenetics controls which genes are on and which are off and you mentioned a couple of genes that are up regulated and presumably those that are downregulated as well is this potentially again another opportunity for therapeutic events and opportunities for identifying particular genes that might be up regulated that

are causing further cartilage or other synovial joint tissue breakdown that could be switched down absolutely yeah these epigenetics regulators they include a lot of proteins but also nucleic acid small arm is another arm is so there's actually a host a whole host of potential ways we could use them there could be classical ways using small molecule inhibitors so classical trucks to affect some of them either inhibit them or activate them depending on what we want to do but then there's also the option to manipulate those rna molecules in a type of gene therapy where we

inject for example some of these molecules into the joint if we design them accordingly we could make them stay there for a long time or being produced they're actually within the joint cells so they are staying as long as we want them to instead of having an injection every few months so there is a lot of potential and again as we discussed before lots of these poachers have been used quite successfully in mice to qoa and none of them has made it yet to humans but i think as keep improving then there's lots of potentials

there yeah it's an exciting time with lots of opportunity for for therapeutic development now frank is there anything else that you're doing in the lab that you're particularly interested in at the moment where you see important potential translational opportunities into the human condition well for my lab we are excited because we are finally increasing our collaborations with clinicians we have a rheumatologist dr tom abbott who is seeing osteographics patients but also working on very molecular mechanisms we're working with a few physiotherapists and orthopedic surgeons so where we are we are trying to do one of

some of those things to create these different fields and translate things faster i think i'm getting more excited partially because of tom's influence about the synovium so i'm a cartilage biologist by training and we know for quite a while now that oscillatory is not a cartilage disease joint disease but my lab hasn't really ventured into the other tissues as much but i'm getting quite interested in the synovium and different both pro and anti-inflammatory mechanisms that we can explore and manipulate to solve osteocritics and also to promote regeneration i think i if we still have to

stop by that cartilage for example does not regenerate and i think there's exciting evidence that this is not true and that we might find different drugs or other ways to manipulate the cells and the tissue to regenerate and allow endogenous regeneration of joint tissues which i think would be very exciting yeah that's wonderful and really exciting work and really pleased to hear that you're broadening from the cartilage biologist into into other joint tissues uh cognizant of the fact that there are lots of tissues involved in this but really pleased that you're also working closely in

that translational space because i think the interactions between those people that predominantly work in the laboratory and clinicians and and other people both in the research and health professional space are so important for us uh developing new insights but particularly their application now frank usually towards the end of the show i usually just try and probe you a little bit more again in part for personal insight but also hopefully because uh the listeners will find it appealing but if you could do anything to improve health and health care what would you do well maybe it

will surprise you because i am a molecular person but i think what we should do especially here in north america we should build more bike paths and more hiking trails and reduce car traffic make people be more active and that's going to have tons of positive influences not only on joints and bones and oscillators but on basically every health aspect whether it's cardiovascular whether it's alzheimer's whether it's cancer even keeping people active and being preventive i think that's would be the i think is the key step yeah there's a lot a lot we can do

about the built environment and access to to green space and transport choices that are more active that i think would have a lot of positive influences on our health in so so many ways again for personal insight but how do you continue to learn in order to stay on top of things within your role well it actually got a little bit easier with kovitch because before kovitz we were traveling once twice three times a month spending half of our life in airports now there is a little bit more time and try to read we go

to selected meetings online meetings seminars learn still what you would learn at the conference but we don't spend all this time traveling and so i i think it's just reading i do i do for example like to do grant reviews i'm on many grant new panels and there you always see the newest even before it gets published you see newest ideas ignorance findings you see what people want to do five years down the road so so i find this exciting and learned a lot it's interesting isn't it the impact of covert and potentially making us

somewhat more efficient by reducing our travel time and also at the same time reducing our carbon impact on the community now are there any patient-friendly resources that you'd like to share with our listeners yeah so i mean i think this podcast is great there's another one which i like and you're probably familiar with it's aoa by kerry costello yeah i think the bone and throat indicate as a number of good postings in the u.s there is the oscar crisis action alliance they have posts we'll include uh some links in the show notes from today's show

for those resources that frank's mentioning now i think my favorite question that i love i love to get into uh with different people is just trying to find out why they do what they do what motivates you to do what you do frankly well i think i'm i'm a scientist and i i like to find out new things and i like to have new exciting findings see problems there try to do that part to help solve them and find the signs findings are important and the other big part for me is working with trainees i

really enjoy working with particular phd students i think they are they come very new to the field and then they grow tremendously over three or four or five years and become experts in their field i i really enjoy that that keeps me going as well yeah i think the younger generation particularly increasing the capacity of the number of people who are in a field who are well trained is so so important and such a fulfilling period of their lives but also fulfilling for us to spend time with them as they grow and develop now if

you could have a billboard with anything on us what would it be and why i might go with the with the slogan oe is a serious disease i think or extending it to the bony joint diseases in general i think they have such an enormous impact those diseases together and they are just not recognized as having that impact if your back hurts if your knee hurts you're not going to be active and then your risk for everything else goes up but i think regarding this give these diseases the recognition and the research funds for example

but all over the attention we need because there's such huge impacts yeah i think in general given the prevalence and the impact that this has on the society it's surprising how passive we are as a whole community about our approach to these problems and the fact that more often than not people are just accepting that this is who they are now and it's part and parcel of growing older but there's so much more that can be done and as you suggest you know potentially pouring that either into their own self-improvement and healthcare change but also

potentially considering philanthropic opportunities to support others who are doing work in this space now is there any one piece of advice knowledge or wisdom you'd like to give to people out there with osteoarthritis i tell them what i tell my mice no i don't tell them anything all right stay active don't don't dress those joints work them and make sure you you're active you keep your weight under control you have strong musculature and use those joints yeah i think that physical activity message is one that we hear on a regular basis and hopefully one that

gets reinforced to the listeners out there and i'm here's hoping that your communication with your mice has similar similar reinforcement there as well frank really really appreciate the time that you spent with us today and thank you so much for the insights you provided uh it's been a great pleasure to chat to you about it it was a great pleasure for me too thanks for having me thanks rick he's hoping that many of you have gained some insights from the fantastic conversation that frank just shared with us we know that animal studies have provided valuable

information on osteoarthritis pathology and with this we hope to propel therapeutic target development specific pathways and molecules have shown promise and provide further understanding of the pathophysiology of osteoarthritis and its genesis we still need however further discovery research to determine more joint pathologic mechanisms and therapeutic targets in specific joint tissues to improve overall health this is a really exciting area one that needs your support and also hopefully one that will provide us greater therapeutic opportunities moving forward thanks for listening to joint action with david hunter if you like our show and want to know more

check out www.jointaction.info if you have any questions you can email us at hello at jointaction.info and follow us on twitter at jointactionorg this podcast was hosted by david hunter edited by vicky duong music produced by jordan hunter the information posted on this podcast is not intended to diagnose treat cure or prevent disease anyone seeking medical advice should consult a health professional [Music] you