Latest / 'Bone Up' / BoneUP Live @ ASBMR 2026 - Part 2

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BoneUP Live @ ASBMR 2026 - Part 2 · 'Bone Up'

0:00
Hello and welcome to Bone Up, the podcast all
0:04
about bones. I'm David Armstrong. Hi and I'm
0:07
Richie Abel and together we're going to bring
0:10
you the latest in bone research. So whether you
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are a patient living with bone disease, a family
0:15
member, a healthcare professional or a scientist,
0:18
you've come to the right place. So if you want
0:20
to learn more about our infrastructure of calcified
0:24
collagen, this is Bone Up. Listeners, hello and
0:52
welcome back to another special episode of Bone
0:54
Up. We're here at the ASBMR conference in Boston
0:58
and we're going to bring you another flavour
0:59
of the talks, presentations and discussions that
1:02
are going on. We hope you enjoy these interviews.
1:05
We really enjoyed recording them. Listeners,
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we're delighted to bring you our next guest,
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Laura John Gregorio, Professor of Kinesiology
1:18
and Health Sciences. Tier 1 Canada Research Chair
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in Bone Health and Exercise Science from the
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University of Waterloo. Thank you so much for
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joining us today. Thank you for having me. Laura,
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I heard you speak many years ago and I've been
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quoting you to my patients ever since, so it's
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a delight to have you on the podcast. That's
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really kind of you to say. So yesterday evening
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we had a really wonderful public engagement session
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for the ASBMR. Lots of local people from Boston
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turned up to hear you speak. and you gave the
1:48
audience some practical advice about how they
1:51
might exercise to improve their bone health.
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Could you just give us some of the key points
1:56
for our listeners at home, because I'm sure they're
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going to want to know. Yeah, so I think the first
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thing is to not just focus on bone health. So
2:02
you want to focus on maintaining the muscle that
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you have or even increasing the amount of muscle
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you have, muscle size, muscle strength. You want
2:10
to stay agile. So you want to train balance so
2:13
that you stay agile and prevent falls. And then
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you also want to do resistance training and impact
2:19
exercise to maintain or improve your bone health.
2:22
So those are really important. If you want to
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do other types of exercise because you enjoy
2:26
them or maybe you want to work on your aerobic
2:28
fitness, fitness or other aspects of your health
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you know certainly you want to continue to do
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those things if you can do them safely but you
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if you really are focused on fall and fracture
2:37
prevention you want to make sure you do challenging
2:40
balance exercises that you progress over time
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and that you also do resistance training exercises
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that you progress over time and that you do impact
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exercise. What is resistance exercise and what
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kind of activities can people do? So I like to
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use the words progressive resistance training.
2:58
And that's because resistance exercise is when
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you are working against resistance. So you're
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holding a weight and that weight is adding resistance.
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Some people use their body weight as resistance.
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You can use exercise bands as resistance or machines.
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But the key term is progressive. And one of the
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things we talk about in the exercise physiology
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world is overload. So you actually want to kind
3:21
of overload the tissues. at an intensity such
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that, let's say I'm doing 10 repetitions, by
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the time I get to repetition 10, I can't really
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do too many more, like I can maybe do one more.
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And that's it. So you really want to kind of
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push yourself to get yourself to the point of
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muscular fatigue or muscular failure. So when
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we talk about resistance exercise, it's not just
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about working against resistance, it's also working
3:45
at high effort. So the idea that you're working
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almost close to muscular failure, because you
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have to kind of challenge your muscles in order
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to get them to build and get stronger. I find
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at the clinic, I think the message that we need
3:58
to exercise for our muscles and our joints and
4:02
our bones is out there until the first fracture.
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And once the patient fractures, then they become
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quite reticent or fearful of exercise. Can you
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give us some pointers that will increase our
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confidence to be able to recommend exercise and
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resistance training even to patients who have
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fractured? For sure. So you do want to have certainly
4:20
a period of recovery where you're not, especially
4:23
for a vertebral fracture, right? So the risk
4:25
of refracture or new fractures is high in the
4:28
period after a fracture. So you don't certainly
4:31
want to jump into strength training a month after
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a fracture. So you do want that time for the
4:35
fracture to heal. But then you can begin to initiate
4:39
resistance. exercise and balance exercise probably
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12 weeks or later as long as pain is well managed
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and you have clearance from your physician to
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do so. I think once people are at a bit higher
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risk, and this is true when people start having
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vertebral fractures, we might take a bit more
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of a cautious approach to resistance training.
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But a lot of it is being thoughtful about your
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exercise selection, right? So choosing exercises
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where you're not putting a lot of... compressive
5:09
loads on the spine right so for example sometimes
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we use something like goblet squats where you
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hold a weight close to your body so you just
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you know you would want to keep the weight really
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close to your body you don't want it out in front
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too much because that's going to add compressive
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loads or maybe you find creative ways to increase
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the difficulty of the exercise without adding
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a lot of weight but certainly you should still
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do resistance exercise and balance exercise to
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improve muscle strength and to improve your agility
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because you want to prevent the fractures happening
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in the in the future My patient who has been
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someone who's been at the gym for years and is
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used to exercise and they fracture, sometimes
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it's easy to encourage them to go back. I have
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patients who've never been to the gym in their
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lives and I'm maybe trying to encourage them
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to think about some resistance training at the
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age of 75 after their first fracture. What can
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I say to them? Or what if they don't want to
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go to the gym? Can they do anything at home or
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elsewhere? Certainly, no one needs to go to the
6:02
gym, right? I think the idea is that you want
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to take the principles of progressive resistance
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training and training balance, but you can adapt
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that to a home environment. I think the challenge
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is that you often have to be a bit more creative
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because you have only the resources that you
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have available to you at home. And most people
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don't really have a knowledge of exercise to
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kind of design an exercise program for themselves
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they get at home. So one thing I would say is
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maybe you as a physician can... kind of do some
6:29
exploration in your community to determine who's
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available as a referral that could potentially
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design home exercise programs. And so you say,
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okay, you don't need to go to a gym. What I'm
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going to suggest is you meet with this person,
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you know, a handful of times, get them to design
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you a home program, and then check back with
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them every few months to make sure you're doing
6:48
the exercises correctly, make sure you're progressing
6:50
them over time. So maybe they can still do a
6:53
home program, but they need someone to kind of
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give them some guidance on what to do. How to
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progress it over time and how to do it safely.
6:59
That's the other thing. Yeah. And people get,
7:01
because people lose confidence when they fracture.
7:03
Yeah. Hopefully they can gain confidence aside
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from the muscle and the bone benefits. They'll
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gain confidence as well, being able to exercise.
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I cannot tell you the number of people like in
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our strength training trials that they come in
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not thinking they can, you know, lift very much
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and they leave and they're like, I. didn't realize
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what I was capable of. And they're able to do
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things that they weren't. You know, I met one
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of my colleagues who's a geriatrician. She actually
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took a day and went to, like... places in her
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community that offered exercise services that
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would be appropriate, met with the people, learned
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what they offered, so that she could create her
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own toolbox for referral. Because we get a lot
7:41
of physicians saying, I don't know what to tell
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my patients. I'm like, well, you really shouldn't
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be teaching them anything because you're not
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an exercise expert, but you should. Just like
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you have referrals to cardiology and other disciplines,
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why not have your toolbox of referrals in your
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community of people you can refer to? And you
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might need to do a bit of work digging who the
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right people are, but certainly. have that toolbox
8:01
for yourself. And even that principle of working
8:04
up to near your maximum. Yeah. You were talking
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about, I mean, people think when you're 25 and
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at the gym, you know, lifting weights, that applies
8:13
even if you're older, you can still work towards
8:15
your maximum and that's... Yeah. So what I usually
8:17
say, I like to use kind of a one or two, what
8:20
we call repetitions in reserve strategy. So you
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kind of work to a point where you maybe have
8:25
one or two left in the tank. So that gives you
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a bit of a safety buffer. So you're not pushing.
8:30
quite to your max. But the key is track what
8:33
you're doing because you do need to increase
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the challenge over time. So let's say you pick,
8:37
you're doing squats with, you know, a 20 pound
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weight in your hand. And you can do it six times.
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So you do that, you know, for a week or two.
8:45
And then all of a sudden you push yourself a
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bit and you realize you can do it eight times.
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Okay, that's great. So now we're going to be
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working at eight times and you still have one
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or two left in the tank. And then a week or two
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later, you've got 10. Once you get to that 10
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or 12, you might want to increase the weights.
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But if you're not tracking that and you're just
9:00
going through the motions and always doing six
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reps or eight reps, you're not going to improve.
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If you're doing something your body can already
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do, you're not going to improve. So it's the
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tracking what you're doing and then progressing
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it over time. And not just the weight, also focusing
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on, you know, thinking about how you're doing
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it because you want to fine -tune your form and
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how quickly you do the movement. Sometimes we
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increase the difficulty of the exercise by getting
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people to do it a little bit slower, right? Absolutely.
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Because if you're controlling the weight a bit
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slower, if you do it really quickly versus controlling
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the weight and lowering really slowly and lifting
9:33
slowly, that actually makes it a bit more challenging
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without increasing the weight at all. My understanding
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is that we should all exercise more, but not
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many people really adhere and comply with the
9:48
exercise. Once you can give people a program
9:52
of exercise that they might be able to do and
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progress over time, are there any things that
9:56
we can do to help encourage people to keep up
9:58
with it and keep going, me included? Yeah, so
10:02
I think a big thing is habit formation. Right.
10:05
So you have to have a plan. You have to have
10:09
backup or contingency plans and goals. You probably
10:12
should monitor what you're doing. Right. And
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then find ways to make it habit. But a lot of
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it is also having realistic goals. So, you know,
10:19
some people are gung ho and they're like, I'm
10:20
going to work out five times a week. It's like,
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OK, well, maybe why don't we start with a short
10:24
term achievable goal of two or three times a
10:26
week? But you can't just have it be sort of this
10:28
vague goal. You have to go, OK. What am I going
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to do exactly? When am I going to do it? Where
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am I going to do it? Use a calendar. Put it in
10:36
the calendar and say, I'm going to do it Monday,
10:38
Wednesday, Friday at 8 o 'clock. And then have
10:40
a backup plan. If I miss one, I have to go on
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Saturday. And then what is it? Write down what
10:44
you're going to do and make it a habit. And then
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keep track. There's lots of great tools, apps,
10:52
and things you can use to kind of keep track
10:53
of what you've done and what you've progressed
10:55
over time. But you have to sort of have goals
10:58
and a plan and self -monitoring. And I like to
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kind of reflect at the beginning of the week.
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Okay, it's Sunday. When are the days I'm going
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to work out this week? What does my calendar
11:07
look like? I also have... you know, flexibility
11:10
in my plan. So I have a whole body workout that
11:12
I can do, or I have a split routine, upper body,
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lower. So if I know I have four days to work
11:17
out, I will do upper, lower, upper, lower that
11:19
hits all the muscle groups. I also have a backup
11:22
plan where if I'm at a conference, for example,
11:24
like I'm right now, I'm not going to get four
11:25
days in. So I have a whole body workout that
11:27
I can do. So having these contingency plans,
11:30
either alternate days or alternate workouts,
11:33
shorter ones that you can do if you can't fit
11:35
in a whole one so that, you know, even if you
11:37
get to the gym for 20 minutes instead of of 40
11:39
at least you've done something but the idea is
11:41
that you have to have those plans. I noticed
11:44
in the talk yesterday that you had some really
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beautiful videos on your website is there anywhere
11:49
where we can recommend the listeners can go to
11:53
get some more instruction on the exercises maybe
11:55
see them visually so they're easier to understand?
11:57
Yeah so exercise pictures and videos are tricky
12:00
because The exercises I would give to, say, a
12:06
55 - or 60 -year -old person who's never had
12:09
a fracture, who wants to try to increase their
12:12
bone density, would be very different than the
12:15
patient you talked about, 75 years old, who's
12:17
just had a fracture. So certainly I can point
12:19
you to places you can find exercise videos, but
12:22
it's really hard for the patient or person to
12:24
navigate which ones are right for them. And so
12:27
I really encourage people to consult with an
12:31
exercise professional. an exercise physiologist
12:34
or kinesiologist or a physiotherapist who specializes
12:37
in strength training, because not all of them
12:38
do, but to design a program for them. coach them
12:43
on how to progress and how to do the exercises
12:46
properly. Because you can watch a video and try
12:48
to mimic the person, but you might not realize
12:50
you're not doing it correctly. So I want to put
12:52
that out there. And perhaps in a way that might
12:54
injure yourself in doing it. Correct. That said,
12:57
you know, so we have a website, boneslab .ca,
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where we have some educational resources and
13:02
information and a blog. I don't have instructional
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videos for exactly that reason. I will say the
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best instructional videos I've seen focused on
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osteoporosis, one of them is... Brickhouse Bones.
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It's a US, it's a physiotherapist. So she does
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a great job of implementing the evidence and
13:20
also keeps track of the evidence. And so she
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has some great free content as well as paid content.
13:26
There's others as well, but that's probably like
13:29
the most thorough in terms of online stuff. But
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I will say I do encourage people to consult an
13:35
exercise professional so that they can get a
13:37
program that's tailored to them. They can make
13:38
sure that they're doing the exercises properly
13:40
and have a plan for progression. I always say
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to people, not exercising is a choice as well
13:46
as exercising. People worry if they exercise
13:48
they may injure themselves, they may cause fractures.
13:51
I always say to them, not exercising is a choice
13:54
as well and is associated with a poorer outcome
13:56
in the long term. Absolutely. I mean, you will
13:59
lose muscle strength and muscle mass with age.
14:01
Your balance will become impaired because you
14:04
have, there's many changes that happen with aging
14:06
that affect your balance. So that increases your
14:08
risk of falls and you will lose bone with age.
14:11
And so if you don't do anything, those will definitely
14:13
happen. If you do exercise, you can prevent some
14:16
of those changes. So there is a risk to not doing
14:20
it. Doing nothing is a choice. Yeah. And the
14:22
thing is, it sneaks up on you. You don't realize,
14:25
but all of a sudden it hurts. to go upstairs
14:27
all of a sudden it's a little harder to do your
14:29
yard work all of a sudden it's harder to lift
14:32
your groceries and then all of a sudden you can't
14:33
do it anymore it's a lot harder to come back
14:35
when you've lost a lot so you know doing that
14:38
small putting that small amount of time in and
14:41
it really you can you can get away you can a
14:43
lot get a lot of benefit out of doing strength
14:45
training twice a week and doing some balance
14:48
exercises a few times a week you don't have to
14:50
be in the gym every day but And just that small
14:54
investment can be huge in terms of maintaining
14:57
your flexibility, your muscle strength, your
15:00
balance, your agility. Great. No, it's been lovely
15:02
talking to you. And it's really important just
15:05
to hear the confidence that you will give patients
15:08
and you will give others to recommend to exercise
15:10
to people. Yeah, I mean, we had people in our
15:14
study, people with low bone mass, over 50, many
15:16
of them in their 60s. We had several in their
15:19
70s. And you have people who started strength
15:21
training, didn't think they could do it. And,
15:23
you know, by the end of the training, they were
15:25
dead lifting over 100 pounds, which is amazing.
15:27
But even people who, you know, people say, oh,
15:30
what if they have joint pain or arthritis? You
15:31
know, we had one woman couldn't get out of a
15:33
chair without using the arms for support because
15:36
she had sciatica and arthritis in her hips and
15:38
knees. And she ended up, by the end of the studying,
15:43
able to do partial goblet squats with 30 pounds.
15:45
And so not only could she now get out of the
15:47
chair, but she could actually get up, lift things,
15:50
was much stronger. So I do encourage people,
15:53
even if you have pain, even if you have other
15:55
issues, there is a path for you. You just have
15:57
to have someone tailor a program for you. Thank
16:01
you very much for joining us today. Congratulations
16:03
on your talk yesterday. It was really well received,
16:05
and we look forward to catching you up maybe
16:07
at next year's ASBMR. Yeah, thanks so much, and
16:10
I'm really happy that you were able to have me
16:12
on the program, and thanks. Thanks very much.
16:15
Great to talk to you. Listeners, we have our
16:22
next guest joining us, Dr. Prem Yadav, Instructor
16:25
in Medicine at Mass General Hospital and Harvard
16:28
Medical School, Boston. Welcome to The Bone -Up
16:30
Show. Thank you for having me. It's a great pleasure
16:33
to be here. Thank you for making the time to
16:36
come. You're local here, so you're calling in
16:39
each day to the conference. You presented some
16:42
work on a condition called achondroplasia. Now,
16:45
that's a rare condition, but it's a condition
16:47
that most people are probably aware of and know
16:50
and see people who have that. So tell us just
16:53
a little about the condition and then the work
16:55
that you did today or that you presented. Perfect.
16:58
Yeah, sure. So achondroplasia is like a... Most
17:03
common form of skeletal dwarfism, where individuals
17:09
with this disease, they exhibit symptoms like
17:13
having disproportionate bones, basically. Very
17:18
short stature. Yeah, short stature. What I mean
17:20
by that is you may say that their upper body
17:24
segment looks normal, but their hand and legs
17:26
are disproportionately shorter. And this condition
17:30
is caused by a gain of function mutation, where
17:34
one of the genes, which basically regulates normal
17:38
bone development, gets over -activated. So this
17:42
particular gene is called fibroblast growth receptor
17:48
3, FGFR3, and there are several mutations in
17:52
this gene, and this is kind of gain of function.
17:55
So each gene has to have a precise function during
17:59
bone development or any kind of development in
18:02
our body. So this gene... In a simple way, you
18:05
can say if we are driving a car, we have a brake
18:10
and we have an accelerator. And we need to use
18:13
both to be driving safely. So FGF receptor 3
18:17
is the kind of brake, basically. So it brakes
18:20
and it controls the lengthening of most of the
18:24
long bones, how much bone has to be elongated,
18:26
so that we have the right proportion of bone
18:30
growth. But in this particular condition, The
18:34
break is like overactive. So you are pressing
18:37
more break. That's why our bones are getting
18:39
shorter. And we are heading towards being dwarf.
18:44
That's a very clear explanation of it, actually.
18:47
And this is one of these rare conditions where
18:49
we actually do know a lot about the genetics,
18:51
as you say. And we've identified some very specific
18:53
genes which we know aren't working properly.
18:56
And I think people's perception sometimes, if
18:59
we're told there's something wrong with the gene,
19:00
is that it's... There's something missing, but
19:03
in this case it's a gene which is sort of overactive
19:05
and is therefore putting the brake on development
19:08
of long bones. So what specifically have you
19:12
been looking at then or how have you been contributing
19:15
to this? Yeah, so I mean this disease is like
19:18
highly studied and there is only one therapy
19:22
which has been approved so far, which is like...
19:26
peptide called cnp analog or vasuritide generated
19:30
by basically being commercialized by company
19:34
biomarine and it does amazing job i mean it improves
19:38
skeletal growth or bone growth to a very great
19:42
or clinically significant amount. But still,
19:45
it doesn't make these individuals normal to their
19:48
healthy peers, basically. So what we did is like,
19:53
we made, first of all, we need a model to study
19:56
this disease. Of course, we cannot do research
19:58
on humans. So we made a mouse model, basically,
20:02
where we use the variant of the gene which causes
20:07
this disease. It's called... glycine to arginine
20:10
replacement at G380R, basically. So we made this
20:17
mutation in mouse FGFR3 gene, and now this mouse
20:21
is like a super small, very dwarf, and it has
20:25
all, most of those achondroplasia phenotypes
20:28
or symptoms which individuals have it, including
20:32
shorter bone, lower body weight, and some craniofacial
20:36
abnormalities. And one of the very critical phenotype
20:41
as well as the symptom individual also has is
20:44
like our base has an opening from where the spinal
20:47
cords come out. It's called like a foramen magnum.
20:50
Yeah. So these individual or kids basically,
20:53
they get like a narrowing of this opening, which
20:57
is called like kind of stenosis, which compresses
21:00
the spinal cord, which leads to the. So many
21:04
behavioral and neurological conditions, basically.
21:08
So our mice recapitulate all these phenotypes.
21:11
And then we took the advantage of very basic
21:15
textbook concept. So most of the long bones in
21:20
our body are getting longitudinal growth because
21:24
of a specialized structure called growth plate,
21:28
which are located at both the ends of long bones.
21:32
where the chondrocytes, which are basically precursors,
21:35
you can say, for making this bone longer. So
21:39
this growth plate is like a very specialized
21:41
structure where chondrocytes are arranged in
21:45
a very sequential manner. At the top of the growth
21:48
plate, you have resting chondrocytes, which are
21:52
kind of a reserve pool of stem cell, and then
21:55
below it, you have proliferative chondrocytes.
21:57
And these are the major driver of... adding cells
22:00
to the growth plate. And then down there, you
22:04
have a further late stage of chondrocytes. They're
22:07
called prehypertrophic and hypertrophic cells.
22:10
So what I mean by that, these cells become very
22:13
large in shape. That's what they call hypertrophy.
22:16
They add a lot of extracellular matrix, which
22:20
adds significantly to the bone elongation. So
22:24
you need these chondrocytes proliferation as
22:26
well as these hypertrophic cells. which are the
22:29
major driver for bone growth. And in this particular
22:33
disease, because of this excessive breaking of
22:37
this gain of function mutation in FGFR3, proliferation
22:40
and differentiation of contour sites, both are
22:43
impaired. And there is another very crucial pathway,
22:47
which is important to maintain this during normal
22:51
development. It's called PTHRP, PTH1R pathway.
22:55
So this signal... of PTHRP through PTH1R promotes
23:01
the proliferation of chondrocytes as well as
23:04
delay their differentiation so that you maintain
23:07
the pool of proliferative chondrocytes and thereby
23:10
allowing normal bone growth. And apart from like
23:15
inhibiting the... proliferation of chondrocytes,
23:19
what this gain of function mutation or extra
23:22
breaking does, it also inhibits this PTHRP and
23:26
PTH1R signaling. So because of this breaking,
23:31
there are two things happening. One is you are
23:33
increasing the inhibitory pathway, which is inhibiting
23:36
proliferation. On the other hand, you are also
23:40
suppressing the pro -proliferative signal through
23:43
PTH1R. So we have a a better understanding now
23:48
why the long bones in people with achondroplasia,
23:51
why they don't grow and develop, and it's because
23:54
there's a problem with the growth plates, and
23:57
you've even drilled in now to the chondro sites
24:00
in the growth plates, and they're not maturing,
24:02
and they're not developing, and they're not differentiating
24:05
properly, and you know the gene that controls
24:07
this. So this sounds quite exciting. We're just
24:09
one step away then from being able to... Do something
24:12
about this? Is that right? Or is that the next
24:14
step? You got it right. And actually, you took
24:17
already. I took the words out of your mouth.
24:20
Yeah, I'm sorry about that. So that's why that
24:22
was my next basically the punch line. So in order
24:27
to make these growth plates normal, we took the
24:31
advantage of normal regulation of signaling pathways,
24:34
crosstalk between them. So we wanted to activate
24:37
this pro -proliferative signal. She's PTH1R signaling.
24:43
And our group at MGH, Dr. Professor Harald Upner
24:49
and Dr. Tom Gardela, they are the pioneer, basically,
24:53
who showed basically the entire endocrine unit
24:57
at Mars General Hospital. This is the place where
25:00
basically all these advancements were made. how
25:03
PTHRP is critically important, how PTH1R signaling
25:07
is important for not only the renal function
25:10
or calcium homeostasis, but also for growth plate
25:14
homeostasis. So we recently basically developed
25:20
another analog or agonist of PTH, which is very...
25:26
I would say highly potent, high affinity ligand
25:29
for PTH1R. It's like a truncated version of PTH,
25:33
which is normally 1 to 84 amino acid long. And
25:37
then there is another short version called 1
25:39
to 34 PTH. But now we made one which is like
25:43
just 1 to 11 amino acid. And we lipidated it
25:47
with some small lipid moiety to make it anchor
25:51
to the plasma membrane, close proximity to the
25:57
PTH1R signaling and induces downstream signaling
26:00
basically for a longer period of time. Wow. So
26:04
we are taking basically two approaches. So first
26:08
we wanted to check whether this approach is really
26:11
useful. Can by activating PTH1R signaling, can
26:15
we improve the growth plate structure? or maintain
26:19
this proliferative pool of chondrocytes. So we
26:22
were very impressed by some previous discovery
26:26
where our group has shown that if you change
26:30
the one amino acid in normal PTHRP ligand at
26:34
position number five, normally it has a histidine
26:37
at position number five, but if you replace it
26:41
with a Ileucine at position number five, it becomes
26:44
more potent and high affinity ligand for PTH1R.
26:48
So we generated this change in mouse, and then
26:52
we crossed these mice with our acondoplasia model
26:55
mice, which already have an extra breaking because
26:59
of this gain -of -function mutation. So we genetically
27:03
enhanced PTH1R signaling by using this I5 PTHRP
27:07
into this mice growth plate. Wow. And that resulted
27:12
into, like, a significant improvement in proliferative
27:15
condensates, overall health of mice, and the
27:18
body weight. Everything was, like, significantly
27:21
improved. These mice were much healthier. They
27:24
were ready to breed. I mean, the mating performance
27:28
was improved. Because before that, we were, like,
27:31
having very difficult, like, time to breed them
27:34
because they were so small. So is this like a...
27:38
Could this be used as a gene therapy? It is,
27:40
but then we went one step further ahead because
27:44
this was a critical, very clean demonstration
27:47
that activating one pathway can improve this
27:51
disease. So then to make it more clinically relevant
27:54
or translational. We took advantage of this,
27:58
our newly reported PTH analog, which is very
28:02
similar to PTHRP, basically, but it has a lipid
28:05
attachment to it. When we started injecting these
28:09
second plesia mice from postnatal day, or the
28:13
day they were born, from day three to all the
28:16
way up to one month, every day by subcutaneous
28:18
injection. This also improved their body weight,
28:22
bone length, very similar to what we got by the
28:25
genetic activation. Because we're already using
28:28
PTH -134 and PTH -RP to treat osteoporosis. So
28:34
that was like a plus or very thought approach,
28:38
basically. These medicines are already in the
28:41
clinic. They are being used to treat osteoporosis
28:44
and some calcemic diseases. I suppose it's easier
28:48
then to prove their safety and you can get them
28:50
into patients more quickly. So this is crazy
28:54
listeners. So what you're saying then is that.
28:56
not only have you developed a new and original
28:59
mouse model for acontraplasia, but you've been
29:02
able to use it to make not one but two treatments,
29:05
one gene therapy treatment and also one PTH molecule.
29:09
And it's crazy. So going forward, do you think
29:12
then that you would have one or the other treatment
29:14
or could you apply them together? Could you do
29:17
a gene therapy and then modulate with PTH in
29:20
order to try and get the... Yeah, so like this
29:24
genetic activation was like the... kind of basic
29:28
proof of principle to be honest because genetic
29:32
therapy is something which is still very encouraging
29:35
but I'm sure everyone cannot afford it and it's
29:39
not very easy to do it especially for this kind
29:41
of disease which are like happening from very
29:44
early stage of development. So having something
29:47
that can be either injected or delivered orally
29:50
makes it like a better therapeutic agent basically.
29:55
We are going to work more on this, our newly
30:00
developed PTH1 to 11 analog to check for the
30:04
efficacy based on the dosing, timing, and other
30:07
parameter if needed by combining some already
30:11
approved therapy or some specific inhibitor for
30:14
FGFR3 that you might need inhibition of FGFR3
30:20
on top of that activating. chondrocyte proliferation
30:24
by PTH1R signaling. So you may want to inhibit
30:28
FGF receptor signaling, but at the same time
30:31
you may want to activate PTH1R signaling, and
30:35
synergistically they may produce additive advantage.
30:40
That's incredible. You're going to have to come
30:41
back and tell us about all of those developments
30:45
and give us an update on your research. Hopefully,
30:48
Judy Keene, if you're listening, you might get
30:51
us back next year. And we can get an update.
30:54
Thank you very much for sharing your work with
30:56
us. Thank you so much, Rishi and David, for having
30:58
me. It was a pleasure to be with you guys. Lovely.
31:00
Thank you. It was a pleasure to hear your beautiful,
31:03
eloquent explanations. Thank you for taking something
31:06
that's so complicated and making it so easy to
31:08
understand. Thanks a lot. Listeners, we're delighted
31:15
to bring you our next guest, PhD candidate Ella
31:18
Chen from CU Anschutz in Colorado. Welcome to
31:20
the show. Thank you, Richie. Thank you, David.
31:22
It's a pleasure to be up here. Thanks for taking
31:25
the time. So we saw your poster. I think you
31:29
did some really fascinating research into intervertebral
31:32
disc degeneration. Could you just explain to
31:34
our listeners what that is? Well, intervertebral
31:36
disc degeneration is a condition of the gradual
31:39
breakdown of the connective tissue called intervertebral
31:43
disc that is placed between your vertebral bodies
31:46
in the spine. And the intervertebral disc is
31:49
composed of several different structures. First
31:52
off are the bony structure called the end plate
31:57
that is cartilagous and that flanks the intervertebral
32:01
disc structure, and it's at the end of the vertebral
32:04
body. And also there is the annulus fibrosus
32:10
that kind of connects the two end plates together
32:13
and encapsulates the gelatinous structure that
32:16
is called the nucleus pulposus that is in the
32:18
middle. And so intervertebral disc degeneration
32:22
is the gradual breakdown of this structure. And
32:26
usually the sequelae of such degeneration is
32:29
called degenerative disc disease, in which it
32:32
can have different consequences, ranging from
32:37
pain discomfort to the... gradual lose of your
32:41
spine integrity and some of the treatments for
32:45
clinically significant cases of intervertebral
32:48
disc degeneration are sometimes very invasive
32:50
and hence there has always been an effort to
32:54
try and understand intervertebral disc degeneration
32:56
and why they happen. Ever since the end of the
33:00
last century, research has shown that there can
33:04
be a quite strong heritability for intervertebral
33:07
disc degeneration as a condition, meaning that
33:09
it runs in the family, and if your parents have
33:12
it, the kids are more likely to have it. And
33:14
in the recent years, there has been a way more
33:18
detailed categorization of this disease, which
33:21
is kind of like an umbrella term that encompasses
33:24
the general loss of structure. In real clinical
33:28
cases, we're seeing phenotypes that is driven
33:31
by the breakdown of the annulus or the breakdown
33:34
of the end plate. And some even say that the
33:37
degeneration of nucleus propulsus, which is the
33:41
central structure, can also lead to the degeneration
33:44
and loss of integrity of the disc. So it is really
33:48
a common phenotype that it will show up in about
33:52
80 % of the population by the age of... 40 and
33:57
50 years old but also it can also show up in
34:01
people who are very very young which is not a
34:04
recent finding but it has been brought to people's
34:07
attention in recent years because previously
34:11
the degeneration of the disc has been thought
34:14
to be a condition that is associated with aging
34:17
which is kind of intuitive because it's a gradual
34:20
breakdown but also When the attention is brought
34:24
to the early onset disease, which means that
34:26
it happens like 20, 30 years at the patients
34:29
that are really, really young, that is also have
34:34
been found that it's highly heritable, this early
34:37
onset condition, and so that there has been discussion
34:41
of whether there is an untangled heterogeneity
34:45
of this disease that needs to be resolved. So
34:48
what do you mean by untangled heterogeneity?
34:50
So you're studying the intervertebral disc degeneration,
34:54
and so, listeners, in your spine you've got the
34:57
vertebrae, the bones, and you've got the soft
34:59
tissue in between them, and you're saying that
35:01
maybe this disc degeneration is partly due to
35:04
the bone, partly due to the soft tissue, and
35:06
in particular the centre of the soft tissue.
35:08
And also the annulus fibrosus. It can be driven
35:11
by any of these parts. These are like ongoing
35:15
hypotheses that need to be tested. But, yeah.
35:20
And just break down this genetic analysis that
35:23
you're doing. Yes. So, as previously discussed,
35:28
this disease can be highly heritable. And it
35:31
can be heterogeneous because it can be driven
35:33
by different things. But it's all... currently
35:36
categorized under the umbrella term of degenerative
35:39
disc disease. But we also know that some of these
35:42
diseases are different. So one way we're trying
35:45
to untangle it is by studying the genetic etiology
35:50
of this disease. the conventional ways to do
35:56
a genome -wide association study in human, and
35:59
we're doing that, but there has been limitations
36:02
to genome -wide association study because it
36:05
is very, very hard to do. to study aging or like
36:09
study in an age stratified way. But especially
36:12
for intervertebral disc degeneration, there can
36:15
be early onset disease and late onset disease.
36:18
So in this GWAS study you're doing then, that's
36:21
a scientific process for identifying associations
36:25
between individual genes and disc degeneration.
36:31
And then I guess you come up with a hypothesis
36:33
that maybe those genes play a role in that disc
36:35
degeneration. genes or genetic elements such
36:38
as enhancers and regulatory elements that doesn't
36:41
necessarily encode a gene. So it's an interesting
36:45
aspect to your research which is you're studying
36:47
both humans and mice and I guess it makes complete
36:50
sense to study a genetic disease in humans using
36:52
humans. So why are you bringing the mice in as
36:54
well? Well yeah we're bringing mice for two different
36:57
reasons. The first one is because we can do actual
37:01
study of aging. in mice. Well, we cannot do that
37:05
in a human cohort. Well, in mice, we have actually
37:09
been able to identify an age -stratified genetic
37:12
etiology between mice that have the same genotype
37:18
at different ages. And so that is like a strong
37:22
support for the current hypothesis that there
37:25
The early onset dysdegeneration and late onset
37:27
age, ageing associated dysdegeneration are two
37:30
different diseases. Oh, wow. And presumably then
37:33
the genes that underlie the early onset in the
37:36
20s to 30s and the ageing onset later in life,
37:39
are they different genes? Yes, they are different
37:41
genes. There's only one overlap in the genes,
37:44
but most of them are distinct genetic signatures
37:47
that we're seeing in the mouse. So I guess then
37:49
you're able, using the human studies to identify
37:52
the genes. that are associated with this disease
37:55
and then go back to the mice and use them as
37:58
your experimental model and look at the development
38:00
of that disease? Yes, because the second reason
38:03
is that mouse model actually has a better sensitivity
38:05
in terms of detecting genetic signatures because
38:08
they're housed in a more controlled environment,
38:12
while in humans there is the heterogeneity of
38:15
trauma. that greatly kind of reduced the sensitivity
38:19
to detect a true genetic condition compared to
38:23
the ones that is resulted from external. Many
38:25
patients listening to this will say to me, you
38:28
know, their back sort of wears out just inevitably
38:30
as they get older, and will often talk about
38:33
trauma and say, well, I had a very heavy job,
38:35
doctor, or I fell off my bicycle when I was a
38:38
certain age, or they attribute it purely to trauma.
38:41
So the idea that there's a genetic element at
38:43
all to... Vertebral disc disease is an interesting
38:46
concept. It is, yes. And to be able to identify
38:55
the genetic aspect will actually help us better
38:57
understand what people are at risk of this disc
39:01
degeneration and what people are at risk for
39:04
more severe disc degeneration that would require
39:08
clinical... which is usually the early onset
39:11
ones. Yeah, because there's this question of
39:13
surgery, because some people will have surgery
39:15
on their discs. As they will say, the vast majority
39:18
of people I would see with indivertible disc
39:20
disease don't progress to surgery, sometimes
39:22
because they have other conditions which would
39:24
cause risk, sometimes because the patient says,
39:27
I just don't want major surgery on my spine,
39:30
I'll put up with the symptoms, and sometimes
39:32
because it comes on earlier in life and people
39:36
don't necessarily want to undergo. major surgery
39:39
because they're not sure if the long -term complications
39:41
of that so this is certainly interesting that
39:44
we could identify genes which would help predict
39:47
all that yes yeah we're trying to identify genes
39:50
that can indicate the risk of early onset and
39:54
hopefully later onset disease fascinating research
39:58
thank you for sharing thank you so much thank
40:00
you very much We hope you enjoyed this listeners
40:06
episode. We've got a lot more interviews to come.
40:09
So tune in for the next part. We'll get it to
40:11
you as soon as we can. We'll see you then.