Where does osteoarthritis pain come from? with Prof Anne-Marie Malfait

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 truths 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 have the pleasure of talking about where does osteoarthritis pain

come from now managing osteoarthritis pain is a great challenge for many of you whether you are a patient or a clinician non-steroidal anti-inflammatory drugs are often used despite their potential risks associated with long-term use in recent years new advances have led to the exploration of centrally acting medications such as deloxetine for osteoarthritis pain despite this those with osteoarthritis continue to suffer from inadequate pain relief and many in the clinical community see pain as a continuing unmet need by better understanding the pathways that influence pain we might be able to better treat osteoarthritis pain by identifying

potential therapeutic targets but on this episode of joint action we are joined by anne marie malfay to discuss where osteoarthritis pain comes from emory's research focuses on pain in osteoarthritis she is the professor of internal medicine and the george w stuppe md chair of arthritis at rush university in chicago anne-marie received her medical degree in 1989 and her phd in 1994 both from gente university in belgium her early research training focused on cartilage metabolism in osteoarthritis her postdoctoral training at the kennedy institute of rheumatology in london focused on the role of cytokines in inflammatory arthritis

in 2001 she joined the pharmaceutical industry joining a team for the development of disease modifying osteoarthritis drugs since 2009 anne marie has been at rush university and established a research group studying pain in osteoarthritis using animal models her group studies the relationship between joint damage and the neurobiologic processes that underlie osteoarthritis pain with the long-term goal to develop more efficacious and safer analgesics and disease modifying osteoarthritis drugs hello anne marie and welcome to the joint action podcast good morning david i'm very pleased to be here and to see you in sydney it's a pleasure to

have you along now the first part of the show i usually try to get to know you a little bit better both for the listeners but also for myself but in the first instance can you just share with the listeners a little bit more about your background and what a typical day might look like for you well i was trained as a medical doctor and i did rheumatology training but very young at a very young age i was actually lured into into the lab literally it was in the basement of the rheumatology division where i

trained in ghent in belgium and so i disappeared into the lab and i essentially never came back out so i really trained as a retrained later as a basic scientist and i did a phd in biochemistry and you know i find it endlessly fascinating to do this job and on a typical day unfortunately as a scientist i am almost never in the lab anymore at this point people in my lab they joke that they don't i don't even know which floor it is on which is probably true but i i really miss going to the

lab so i spent all my time in the office pre-covered i would travel a lot which i would go to conferences and meet with people everywhere around the world but in the last 18 months like most people have actually been bound to this chair here and i do i do office work so typically in a day what i what i try to do i am not a morning person so i do come quite early actually but i do all the sort of menial boring things first i do emails and administrative things so that by the

time it's it's lunch time or so i have that behind me and then i always look forward to a whole long afternoon of doing exactly what i what i like doing which is reading papers writing papers meet with people in the lab i have one-on-one meetings with them quite often there are about 10 people in the lab so that takes quite a lot of time i like to mentor young researchers and so i will meet with them either live or or more recently on zoom i do a lot of editorial work also so i do

review a lot of paper i'm an associate editor for two journals so i review papers i review grants so that's really what i do mostly on on a day-to-day basis i i i handle about five to ten papers a week of other people so that's something that i do and then wednesdays like today is a wednesday it's actually one of my favorite days in the week because then we have our weekly lab meetings and that's always very exciting because that's where the people in the lab present their ongoing results new findings and we discussed them

so we just had one today and that's something i actually always really look forward to so that's that's it it's unfortunately quite a sedentary life especially now at this time fantastic emery it's a it's a wonderful explanation i might just dig into a couple of those topics a little bit more if that's all right but really interested in i guess the journey that's taking you from the basement so to speak where you were presumably in the lab the majority of the time to now where you predominantly in the office and meet with people in the

lab face to face how long did that process take and you know what led to that and obviously you miss it but are there other elements of it that you think you're potentially more influential in that still allow you a presence in the lab without you physically being there yeah that's that's a it's a good point first of all it took a very long time just if you talk about timing so i did lab work for a very long time myself and because i changed jobs quite often for example i spent almost 10 years working

in the pharmaceutical industry in the first decade of this century you know there i started off again being in the lab quite often when there are new techniques up until quite recently i would often force myself to learn them i think that's quite important that you really know it's only really very recently that the really new techniques i don't do them myself anymore sometimes also because it's very precise when we do surgeries on mice for example to model osteoarthritis and these are very fine surgeries under a microscope often where we look we also dissect nervous

tissues and so i say we because they do it i have not actually done this because i don't actually see it anymore myself at this point so at some point you have to let go but i do believe that and i think this is true for many basic researchers that if they have done it for so many years that they really understand specific difficulties and so i do spend a lot of time speaking with people and going over experiments and asking them details where they really feel that i have i have done this in the

past a lot you know that i i often tell them you know don't don't worry i know how difficult this is um and and that this very often fails because i i think a lot of people do not always realize how many experiments in a lab really fail so and i do i do pop in there and and have a look at what the different people are doing and connect uh people with each other in the lab where i see that this particular person is very good at at specific techniques everybody has their strengths some

do surgeries some do behavioral essays and mice others are very good with molecular biology which is very specific so you can connect people with each other they have their different personalities and when you stand back you can actually sort of have a an overview and see this and and bring these specific skills together fantastic and i might just pick up on one more point while we're doing this is the the the time that you spent in industry is of obviously a relatively unique experience for someone who's now predominantly in university and academia what what particular

skills strengths techniques do you think you picked up there that you found particularly helpful in the academic space the main one they're two actually main ones and i think is that in industry is very result driven right and you are always accountable one is always accountable to management i cut the bottom line is that something has to happen at the end and so one has to be very result driven with timelines and be very strict following these timelines one has to be able to cut one's losses if something doesn't go anywhere and in order to

meet these timelines that's actually point number two is that the work is very team oriented in industry and that i have really learned a lot from when setting my own lab up here is our lab is really team driven in that you know it's not about this one star person it's not about me it's not a bad one the one person who's the best is that we all really work together so when we when we actually publish a paper one can often see that almost everybody is on that paper uh if they've really done something

and and we really can all of a sudden just like we had to do when i worked for industry say now we are very close here with this paper we will all benefit if we can bring this out or this particular grant and then everybody drops everything and they work on that to to bring that together and that's how we worked in industry and and so we do this here and it it seems to work and and everybody seems to enjoy it actually yeah i think when there's a team working together and there's a lot

of collaborative intent and you have similar goals there's i think a lot of enthusiasm and positive culture that gets brought to that work environment now just digressing from work for a moment when you're not doing your day job what is it that you like to do oh well my the main thing that i like to do when i come home is that i really do not want to look at screens so i we barely watch any television and home i don't even want to go to the cinema anymore while i love reading i find it

currently hard even to read because there's just simply too much screen staring going on so we i i listened to music pre-covered we would go to concerts all the time and nowadays we actually always listen to the radio and we we put on we get old old records out and we listen we basically listen to music almost non-stop wonderful and what sort of music is i guess your favorite genre classical music actually yeah listen mostly to classical music although my husband has a huge collection of old vinyl records and so one game that we played

in the during the whole lockdown in the past year and it was fun we we brought them all out from the basement and it's a very you know it's his collection and i would say it's eclectic it's it's more than classical music there's all sorts and so we would play this game where we would take the top record and the first one in the stack and and we had to listen to at least one side like it or not so we went through hundreds of records over many many weeks and i discovered a lot of

music that i don't like but it was fun well hopefully some music that you did like as well yeah absolutely yeah mary if you had to describe yourself in five words what would they be yeah that's a difficult question so the first word that came to my mind when i saw this question was relentless but then i also i decided that you know uh to focus on on uh positives you know there there's plenty of negatives but i'll so the the positives i would say are thoughtful independent loyal and optimistic i think if you work

on osteoarthritis you have to remain optimistic and you have to be relentless so you have to keep going to be tenacious essentially yeah they're all they're all wonderful qualities and as you say i think for someone who's engaged in the osteoarthritis space some of them are probably more important than others and i i would have thought as you said optimistic is incredibly important but i would have thought to me relentless is actually very positive quality um because i think in this in this space i think a lot of people sometimes lack for resilience um and

they take uh rejection which is quite common in our space whether that be through manuscripts or grants or whatever it might be in a bad way true and it's one of the hardest things about i mean i think our job whether it's clinical or basic research is is totally and utterly fascinating but i think very many people do really not realize how we deal with rejection and failure a lot a lot experiments fail and then when they work then you write them and and they get rejected or people you know i'm always when you go

to concerts and musicians at the end of a concert that they get standing ovations and everybody claps and we get most of the time you just get rejection you know it's very rare that all room stands up and claps right so it takes a special person to keep doing that i think yeah there was a there was a really wonderful moment in the wimbledon final with the women's final recently where the person who is responsible for making the astrazeneca vaccine stood up and got a standing ovation and had a standing ovation i saw that too

that was wonderful huh yeah yeah you know huge huge credits them and wonderful accolades for what they've been able to achieve to help us get out of this pandemic now the main content of today is obviously picking your brain as an international expert in osteoarthritis pain about where that pain might come from and particularly your insights that you've gained from many years working in this space but in the first instance i might just try to create a little bit of context as to how osteoarthritis pain is characterized uh just to give us i guess a

broad overview of that idea so for patients who have osteoarthritis really patients and everyone working in this space really has to realize that osteoarthritis is a disease that is chronic progressive and that can take years to even decades to to keep progressing and so the character of the pain and the character of the disease is also progressive and can really change over time and it's been maybe only about 20 years or so that people have really started to document what that pain exactly looks like and and so people really see that it is progressive and

very typical in early on in the disease patients will say that this pain has a mechanical character and so what that means is that it will be brought on by specific activities loading on on the knee for example people will say that it hurts when they go up the stairs and i always give the example about i actually became interested in osteoarthritis because of my grandmother she had very severe generalized osteoarthritis when i was a child and she she would actually plan her activities upstairs so that she'd only have to go upstairs once in the

morning and once in the afternoon so make the bed do other things wash all in this one grouping so that she could avoid going up the stairs actually because that was so painful so then typically as the disease progresses what will happen is that this pain can can start radiating outside the affected joint and then it can become gradually more severe and people with with more end stage osteoarthritis can have really pain pain flares at night they can wake up with severe pain and and so that's the pain experience to a patient but then as

a clinician or a researcher one can also start detecting specific signs that come with this pain which maybe we can talk about the mechanisms of that a bit later but there's this particular technique that's called quantitative sensory testing and so people can for example see what a pain pressure threshold would be so uh what what what the researcher can do is is really put a certain amount of pressure say on the on the affected joint on the knee and see how much pressure it takes for pain to be felt by the patient and so typically

in a patient with osteoarthritis these pain pressure thresholds will be lower and that's called calalodinia actually so there's a sensitivity to mechanical pain and and not only is this present at this at the site of the affected joint but this can actually be present in other places so people who have pain who have very bad osteoarthritis in the left knee for example will have lowered pain pressure thresholds in the left knee but they can also have this in the left ankle or even in the right ankle so there is a sort of generalized hypersensitivity that

occurs and and that is um more recently this has been very much uh appreciated actually by the osteoarthritis research community now what's very interesting is that pain experience is of course very individual to each patient and and the way this progresses over time is not as clean as i just sort of listed it but this can be really affected by very many different things by the patient themselves by factors such as obesity or genetic factors because people experience pain individually very differently based on certain genetic variations difference between just simple things whether one is male

or female there are many different things comorbidities people can have as people age people can develop things like diabetes and other comorbidities accompanying illnesses that affect the pain experience wonderful that's a fantastic explanation and one of the one of the obviously assessments for the quantitative sensory testing that you brought out is to look at sensitization um and can you just tell us the difference between peripheral and central sensitization and what actually is changing to occur with the peripheral and sensitization from a biologic functional perspective yeah so to really grasp that one has to first have

a little bit an idea of the very basic template of how pain is sensed and it's actually a very simple thing pain is something that is very important to all of us it's a basic survival mechanism it's what tells you that you shouldn't touch a hot flame or or whack yourself with a hammer say because you know it hurts and and you can break something so there are specialized neurons that innervate our skin and the joints and they they are specifically equipped to to detect these potential harmful stimuli such as high heat for example and

so these specialized neurons sensory neurons are called nociceptors and so they they are very abundant everywhere in in the body especially in the skin but also in the joints and they innervate different tissues in the joints and their cell bodies are are in the periphery they are located in specialized organs that are called dorsal root ganglia and so the cell bodies are there and so they they actually basically innervate the peripheral tissue and they also send an axon it's called to to the spinal cord to the dorsal horn of the spinal cord and and there

they make a synapse with what's called secondary or second order neurons that then take the pain signal up to higher regions of the brain so that's the central so what happens is in just an acute potential harmful situation is that one can touch a hot flame for example and there's a very rapid uh signal in the form of an electrical an action potential so it's an electrical stimulus so it goes very very fast the signal transfers to the dorsal root ganglion and from there to the spinal cord and higher regions of the brain where you

can then uh consciously detect that and interpret it as pain and then very rapidly have a reflex you withdraw your hand and that's it now in when you have a more chronic disease such as osteoarthritis where you have ongoing changes in the joint and in different tissues in the joint is that you have continuous what's called continuous peripheral nose deceptive input so put continuous pain triggers that go there there's a constant barrage and so what happens is that the pain signal gets amplified actually and this can happen in the periphery so that now means that

there are changes in these in these dorsal root ganglia so that that the threshold for activation of these neurons lowers so we are all very familiar with that for example in the case of sunburn when when you have sunburn when you normally touch your skin that doesn't hurt but when that skin is burned by the sun that really hurts so that's that's called that's actually peripheral sensitization because these nerves there are sort of on high alarm and and they tell you so again this is a really protective mechanism because what it what it does it

make sure that you don't keep rubbing that skin that is sunburned and so you actually allow that skin to heal so again it's a protective mechanism now when it all takes too long and it keeps going then you start also having really profound changes in the central nervous system and this can happen at different levels it happens in the dorsal horn of the spinal cord but then it can also start happening um higher in the brain at different levels of the brain and that's what's then called central sensitization and in some instances and it's not

very clear yet when this particularly happens and to whom that particularly happens but so it can happen actually that this that this constant input from the joint and the peripheral input versus the central sensitization mechanisms are uncoupled and and then those are probably um unfortunate for for people where this happens right where this where there's this uncoupling and there's no obvious connection anymore between the pain and what's really going on in the periphery that's a fantastic explanation hopefully uh helps people to understand where their pain may be coming from now in the context of osteoarthritis

whether it be through changes in the periphery or centrally are those changes reversible i think that we have a lot more evidence so first i would like to say that in osteoarthritis the good news is that in the vast majority of people it would appear that the main driver of chronic pain comes from the periphery the main drivers come from the periphery so the best argument that one can make for that is that if somebody has very bad knee osteoarthritis and they get a new need i get total knee replacement that in the vast majority

of people around 80 of people that actually effectively takes away the pain but not just that so one can detect measures of or signs of peripheral and central sensitization can be detected as i talked about earlier with the quantitative sensory testing so if people have these lowered pain pressure thresholds we talked about is that it's also becoming clear that if one takes away the disease so to speak joined that these measures are also reversible and there's some very interesting work that has been done where people do brain imaging and they have really seen that people

with chronic pain and people with chronic low back pain people with knee osteoarthritis can have real changes that can be detected in specific regions in the brain by say by functional mri and here again these changes are actually often reversible there's sometimes a quote that i i look at so that i think is applicable here so um i i guess you're familiar with ramon icahull who who was a spanish scientist who is often credited to be the first neuroscientist he won the nobel prize in 1906. so he basically mapped all neurons in the brain and

he made these beautiful drawings art of neurons and and he for the first time described what was called this uh synaptic plasticity so when one talks about the nervous system whether it's peripheral or or central the one thing that is really striking is is a tremendous plasticity it changes all the time and he was one of the first ones more than 100 years ago or the first one to really appreciate that and there's this fantastic quote by him that says every man if he so wishes can become the sculptor of his own brain and and

i think that's a very positive message because if if the brain can be trained to learn chronic pain i think that the brain can also be trained to unlearn it and and this plasticity has been quite well described centrally peripherally it's less clear at this time yeah wonderful now with that plasticity in mind and the wonderful quote that you just spoke about and thinking about the pain that comes from osteoarthritis and the work that you've done in the lab what treatments are currently available to help modify that pain and what ways do you think we

should be modifying those treatments based upon insights that you've gained from the lab so the treatments unfortunately that are currently available to people are quite limited so pharmacological treatments the standard pain treatment is is actually non-steroidal anti-inflammatory drugs and overall they their efficacy is is moderate at least over a long time especially in in people who are getting older come with a lot of side effects they're hard to tolerate for gastrointestinal side effects and then many people resort to opiates but it's actually been shown that opiates apart from all the unwarranted side effects and and

the risk for addiction it's also been shown that they are probably not even that efficacious in in osteoarthritis so the the pharmacological arsenal is actually not big for osteoarthritis and and so there's a real need for the development of more targeted therapies and so your question was you know what could they be so i i am personally very optimistic that we can really focus on the periphery here because as we've already discussed there's a lot of clinical evidence that that there is a very strong peripheral drive to the chronic pain in osteoarthritis and so using

mouse models the the main lessons that we are currently learning in our lab and in in other laboratories using mouse and rat models is that again that there is this tremendous neural plasticity that is going on we've already talked about neuroplasticity in the brain but it turns out actually that there is also this tremendous neuroplasticity in the joints these observations are quite newer so there's actually neuroplasticity at different levels in the joint and and using mouse models one can really look at that in great detail so briefly these three levels of neuroplasticity there are three

levels of neuroplasticity our first is a functional neuroplasticity so if you if you look at that you can you can develop we have developed these neurobiological methods to look at activity of joint uh afferents they're called so the the sensory nerves that innervate the joint in a mouse and so what we see that in the course of osteoarthritis there are specific nose receptors that are becoming really sensitive to specific stimuli so we can squeeze the knee of a mouse with osteoarthritis and then we can go look at the cell bodies in those dorsal root ganglia

and then we can really see that there are nerves there that are now reacting to that squeeze that don't react in healthy mouse joints so that's what we call functional neuroplasticity so we can then go look well what causes this and what sensitizes these specific neurons and for that we can we can do molecular studies so that's the second level of of plasticity is a molecular plasticity that is going on so we really can see now that the molecular phenotype as we call it of these neurons completely changes in the course of osteoarthritis so these

these nerves start expressing completely different molecules and and they can have specific receptors that were not there or that are not there in a healthy joint it sounds complex but it's actually something that we can leverage because we can now go after these specific receptors and maybe selectively target these specific receptors and that would then maybe lead to potential drug development but really the most fascinating thing that we are finding is an is a very profound anatomical neuroplasticity so what we are seeing is that if you have a healthy mouse joint then there are specific

nose receptors that are innervating specific tissues in the joint the synovium for example cartilage does not have any neurons that has been well described over many decades now but what we are seeing is that as the joint remodels is that there are new nociceptors that are sprouting in places where there shouldn't be any and so in the the subchondral bone for example which is the bone that is just underneath the cartilage is now starting to remodel and there are channels in that subchondral bone where new nociceptors new nerves are sprouting so one of the things

that we are trying to do in the lab is to really characterize in great detail where these nerves are exactly what type of nerves what exactly do they just express molecularly and how do they functionally change in the course of osteoarthritis and so in that way we hope that we could start really targeting very specifically those nerves that are in the right place to cause the pain of osteoarthritis and yes this is in mice but this can be validated in humans um also now that's wonderful and it's really exciting to see such developments happening and

from the viewpoint of you mentioned the the anatomic changes that are occurring within the nerves from a molecular standpoint are there particular molecules that you think are particularly exciting that might be better targeted towards some of those changes that are occurring that are pathologic as opposed to physiologic and normally functional whether these molecules have been understood and better developed and and targeted with current treatments or should we be looking at new waves of treatments coming through to specifically target those molecules and if you want to talk about you know things like nerve growth factor and

trap kinase and other things there that that would be great so let's talk first about the growth factor that um so just to give some background to that nerve growth factor is a specific growth factor that as the name says you know in in embryos actually um is is really essential for the growth of sensory nerves and it was discovered about 20 years ago that in an adult organism nerve growth factor is key for pain and when you inject a nerve growth factor people have actually done that in the skin of humans that causes rapid

pain but also long-lasting pain people have really in the past 15 years have started making antibodies to neutralize the effect of nerve growth factor and nerve growth factor causes a lot of its pain producing effects through binding the receptor that is called trick a tropomyosin receptor kinase a and so when ngf binds this receptor called trick a that is actually what leads to densitization and pain and so when antibodies are being given that sequester nerve growth factor then this binding cannot occur and there's been a lot of excitement in the past decade with antibodies such

as tenezumab and fasinumab made by regeneron so a very large clinical development program exists for for these antibodies and they hold tremendous promise for the treatment of pain in osteoarthritis unfortunately binding or sequestering nerve growth factor comes with an unanticipated side effect in that during these very large clinical trials it was observed that quite a few people actually depending on the trials develop what's called rapidly progressive osteoarthritis so for some reason that is currently not at all understood people who receive these antibodies would all of a sudden develop a lot of pain and very rapidly

progressive osteoarthritis that actually necessitated replacing the joint unfortunately the mechanisms of that are not understood obviously there's lots of theories that are around and you may not necessarily want to expand on this as to why that rapidly progressive osteoarthritis may occur including you know co-administration with anti-inflammatories people having some pain relief and being able to increase their physical activity their jointness not necessarily being functional to undertake those loads but there's also probably more interesting theories about you know the role that this may have physiologically as nerve growth factor particularly in the subchondral bone what what

are your thoughts and you know how do we best continue to explore that area because you know it's obviously on the cusp of either fda approval or not for those agents and there's been as you mentioned decades of work gone into that space and lots of insights that we've gained but i think the critical insight is how do we best identify those people who are really at risk of that and what is it that they're at risk from exactly and i just want to let you know that we actually are about to start the whole

research project on this again in mice so going back to an earlier question so that you asked you said are there specific things that you can target specifically in joints with osteoarthritis so going back to this whole neuroplasticity thing is that a joint with osteoarthritis is different than a healthy joint right so there are nerves in different places and nerve growth factor itself is probably not present in a healthy joint so it's it's something that is being made by a joint that has osteoarthritis and it's our hypothesis actually that it's possible that nerve growth factor

is what is uh responsible for the the sprouting of the new nerves in the joints that we have seen although that has not been proven yet but and it's entirely possible and and that there is some nice work out there that suggests that these new nerves that are growing and nerve growth factor itself may actually really be very important for joint health so they may really have a homeostatic role so if we see that there is subchondral bone remodeling for example as very much as a part of osteoarthritis and there are nerves that are sprouting

then there these nerves feel the pain and as we've already discussed the pain itself has a protective role but then there are also nerves that are growing and it's quite clear actually that nerves also have what's called a trophic role in a joint so the nerves may be there because they help bone especially maintain its integrity and there are groups that have studied that you really need new nerve growth for example in models of fracture repair in a mouse so it's entirely possible that we really need those new nerves not just to feel pain but

also to keep the joint healthy now again that sounds like well then maybe this is not such a great pathway to target but i actually think it is it's just that going back to what we already talked about these nerves are not all created equal there are different types of nerves and now with very new technologies people people can really and we do that too you can really start to in great detail characterize these different nociceptors at a molecular level and then it turns out that you know up until only a few years ago people

would say there are only two types of nociceptors c c fibers they are either peptide non-peptidergic and those were the two classes and that was it now with all this very detailed molecular profiling by doing things like single cell rna sequin it actually turns out that there are many more functionally distinct nociceptors at least probably 12 different classes and so we can now really find out are there specific subsets that are specifically growing say in the subchondral bone and sprouting and causing the pain there and then maybe those express trick a or maybe they don't

and so we can really probably go into that pathway and see exactly where is ngf active and on which subsets of nociceptors and then we could probably really exploit that to just target that same pathway and that same signaling pathway but then a little bit a more specific and detailed manner yeah i know it's a it's a it's a wonderful story and hopefully something that will lead to uh revolutions in the way we treat and manage patients but i think a critical element along that journey is really understanding the heterogeneity of the disease the pain

experience and stratifying yeah i agree so i i'm really worried that this with the whole ngf trick a story that we don't want to throw away the baby with the bath water really and clearly for the vast majority of people this this this is something that really helped with their pain without causing rapidly progressive osteoarthritis so i think what we can focus on is to really see can we characterize something is there something about those patients that can give us a signal and i think we can actually we could really find out specifically maybe they

have a specific subset of neurons in a part of their joints that at that point was really important to me it's very important that this is a chronic progressive disease and a knee joint early versus mid-stage versus late-stage disease will look very differently from an a neuroplasticity viewpoint too and so there's i think there is a critical window where we do not want to mess with the ngf trick a signaling but all the other times we probably can and that's what i think we should focus on and is that the focus in part of what

you're planning to work on with the new program grant that you've got emery uh yes absolutely so one of the things that we do not understand for example is where exactly is ngf expressed in the joint and and the receptors it's not just the receptors for nerve growth factor are present on neurons but not just on neurons different joint cells can respond to ngf chondrocytes cartilage cells can different cells in the bone can there's also a very big interest currently we haven't talked about that yet but it's the the contribution of the immune system to

pain so it turns out that and there is an influx of macrophages and other immune cells in the joint with osteoarthritis but also in the dorsal root ganglia so in the nervous structures and then so these immune cells interact with nerves and so so these neuroimmune interactions are also something that continuously modify uh the pain signals and and can contribute and be pro lg6 or pain producing but they can also try and dampen the pain and so these things really progress over time and so that's that's to me it's one of the most important things

about osteoarthritis it's not static that but it changes the whole time and if we can find markers where we can say this particular pain experience these types of quantitative sensory testing outcomes really tell us what stage this person is in in a mouse we can do all that now we are trying to we are starting to get there now we have to find out how we can translate that to a human being but then we can probably start identifying patients where we should not say target nerve growth factor yeah no it's really exciting and hopefully

lots of revolutions to come in in this space now i haven't managed time as i typically don't very well and uh we're probably running a little bit short on time but any particularly meaningful insights that i didn't ask about that you think are really exciting that you think people out there with osteoarthritis might like to know before we move on to the next segment well i think what's exciting is that so i have been working on osteoarthritis now for a long time and i do think that we are entering a new era now that there

is really cause for optimism as a community clinical and basic researchers together have really in the past few years made enormous progress i think in understanding what's going on in joints with osteoarthritis how the pain progresses and and mechanisms there so i do think that there is real possibility here for more targeted therapies and i really think that we are probably not too far off from making real breakthroughs superb it's great to hear because i think at the moment in many instances from a pharmacological perspective we're treating this disease with a hammer as opposed to

a more precise targeted treatment now what i usually like to do towards the end of the show is close with a few questions to get again to know you a little bit better and the first instance is just a rapid fire round with some quick questions about things that interest and appeal to you so favorite book yeah i like to read but i don't have a favorite book i read fiction and um i mean i have a lot of books and a lot of favorite books so um poetry i actually read poetry superb favorite movie

uh baghdad cafe correct it's a road movie i like road move dog or a cat person cat favorite quote it's a quote by henry david soro it's actually hanging in my living room and it says disobedience is the true foundation of liberty wonderful what's your favorite food radishes cucumbers and oysters they all happen to be low calorie but i eat radishes daily i'm pretty sure if i asked that question a thousand times i would not get that response again [Laughter] do you have a bad habit no not at all come on i have no bad

habits where would you like to go on holiday i i'm dreaming of making a trip around the world once i would love to do that sounds like a great idea now if you had a superpower what would it be time travel i would love the time travel forwards or backwards back no i have no interest in going forward at all you don't want to know what's going to happen no at all if you could meet anyone dead or alive who would it be probably a musician like gustav mahler and his wife alma if money were

not an issue what would you be doing for my personal use i know exactly what i would be doing i would be living in a hotel as opposed to in a house like you could see that in these old ladies in old movies they would they would sort of you know live in in the waldorf astoria or something it wouldn't have to be that one but a nice old grand hotel and i like the idea of not owning a house and not owning anything and at the same time you know have this space to myself

and that's probably what i would do from from a purely egocentric viewpoint if i were really rich i would probably then sort of start supporting the arts and things like that wonderful all right now a couple of closing questions why do you do what you do what motivates you well i think um i think it's very clear that being a scientist is just endlessly fascinating actually and specifically this osteoarthritis i that's what i've been doing now for so long i think it's just endlessly fascinating i find it remarkable that one can do this one's entire

life and then on a daily to weekly basis discover new things about this and it's so much fun to learn new things and to to meet people from all over the world who also have this weird interest in in something and and and one can discuss that and and and that's really why superb now if you could have a billboard with anything on us what would it be and why well in the context of osteoarthritis i would we haven't really we've only talked about new drug development and so but the one thing that really does

work for osteoarthritis is losing weight and exercising and so i would probably put on the billboard keep moving [Music] because that's something that you really see as as you know and i do not myself see patients but all friends and family and as they get older they all call me and they all have osteoarthritis and they have pain and i i'm really quite surprised actually and a lot of my families in europe and how they are really not aware of the fact that they should and can lose weight and that will help them and they

stop walking because it hurts to walk and um so do your 10 000 steps and keep moving that's what i would write on the billboard wonderful anne marie thank you so much for coming along it's been a great pleasure to have a chance to chat to a little bit more and uh to spend a little bit of time together well thank you that was fun i hope to see you in sydney or you come to chicago at least in some part of the world when we're allowed to travel a little bit more yeah that will

be wonderful thank you david i hope you found the content of this week's podcast recording very helpful in going through how osteoarthritis pain is characterized the differences between peripheral and central sensitization some of the changes that are occurring in nerves and more importantly some of the treatment options that are being developed to help people with symptoms hopefully in a more targeted and stratified way we recognize that there's lots of different opportunities for you to get treatment for pain for your osteoarthritis and don't just rely on pharmacologic options at the moment we're hoping in the future

that we will have better targeted treatments that are safer for your osteoarthritis management but please bear in mind in the interim there are lots of options that are available for the management of your osteoarthritis pain please don't forget to rate us if you like the show we really rely upon that to get the word out about the podcast thank you again so much for your continued support and i look forward to speaking to you again soon thanks for listening to joint action with david hunter if you like our show and want to know more visit

www.jointaction.info if you have any questions you can email us at hello at jointaction.info and follow us on twitter at joint action org this podcast was hosted by david hunter edited by vicky dwong 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