Connective tissue disorder

So for those of you who don't know me, I'm Diane Celaya. And actually I don't teach a lot in first year, but I teach quite a lot in third year. You probably won't have seen me for couple of years after this lecture but then you probably see quite a lot of me in 30 years.

So today I'm going to talk about connective tissue so I'm going to give you an overview of connective tissue and I'm going to talk a little bit about pathology associated with connective tissue so I'm going to talk a little bit about connective tissue injury in various scenarios as well as connective an understanding of how connective tissue functions in the context of pathology, so in the context of a disorder or disease, you obviously have to know a bit about how it functions in health. So that's what I'm going to talk to you a little bit about at the start. So what are the learning objectives? So the learning objectives are to gain an understanding of the role of connective tissues in health and disease, and so within that what I want you to do is understand the supportive and protective function of connective tissue, as well as understand how they are involved in disease and injury. Secondly, to understand the structure and function of the various types of connective tissue. And within that, the key thing is to identify key structures of connective tissue, but also relate them to function. And finally, what we wanna do is identify the unique features of the properties of the various connective tissue types. And part of that really is understanding how the intracellular matrix differs between the different types of connective tissue.

different types of connective tissue. And then you can begin to gain an understanding of the cells that underlie connective tissue function and each type of connective tissue has distinct and unique cells which help it to carry out its primary function. With the exception of fibroblasts which are involved in a range of different connective tissues. So what is connective tissue?

So what is connective tissue? So fundamentally we know that connective tissue is one of four major types of mammalian tissue. So you've got the epithelium, the muscle, the nervous tissue and finally connective tissue.

And that is what we're going to be studying today. So connective tissue is a material made up of fibres forming a framework and support structure for body tissues and organs. So it surrounds many organs actually, so we don't realise that connective tissue is present in a lot of different organs and it actually helps to protect the organs and provide some sort of structural support to the organs as well. So connective tissue is derived from the mesoderm in terms of developmental differentiation and And that is, of course, the middle germ layer in the embryo. Why connective tissue is unique amongst the various tissue types is that it synthesizes and secretes extracellular matrix. And this extracellular matrix consists of fibers, ground substance, which includes protoglycans of glycoproteins but others like agriculture, which I'll talk a little bit about later, as well as interstitial fluid. So, connective tissue is unique in that it's not just the cells within the tissue that matter, it's more actually the other things that matter. So, what the cell is producing and secreting, the fibers, the glycoproteins and the interstitial fluid. And those are what give connective tissue the unique properties that we have come to associate with them.

And connective tissue have quite a range of functions depending on where they're located in the body and the type of tissue.

depending on where they're located in the body and the type of tissue. So structural, mechanical, protective, transport, nutrients, storage of energy, defense against pathogenic organisms, tissue repair, thermogenesis insulation. So basically anything that you can think of in terms of a function of a tissue then you've got it here. Can anyone give me an example of a structural function of connective tissue?

Who can give me an example of how connective tissue function in structural support?

function in structural support? So both is a connective tissue and of course structural support is a key element of though mechanical who can give me an example of mechanicals yeah joints perfect yeah so joints of course basically their main purposes for mechanical support allow you to move effectively.

support allow you to move effectively. How about protective? Yes bones again protective yeah so the major organs of the thorax, the skull obviously protects the brain, and bone is a good form of connective tissue. How about transport of nutrients and metabolites?

metabolites? That's a bit trickier. Blood vessels. So blood is actually considered a connective tissue and so blood is a good one. Also bone marrow and underneath the skin, so underneath the epithelial layer of the skin you've got different types of connective tissue. Part of that function is the transport of nutrients that support the basement membrane as well as the the overlying epithelial layer.

And again storage of energy, who can give me an example of connective tissue that functions in storing energy.

Fat is also a kinetic energy and one of the key functions of fat is to act as a reservoir or excess energy as we know.

or excess energy as we know. We can also take off something else with that, one of these, which is actually two of these, two of the remaining functions. Thermogenesis and insulation. Perfect, thermogenesis and insulation. So that actually is quite versatile. So it protects us from the cold and it helps us to generate heat. But why does fat help us to generate heat? How does it do that? Yeah, it increases metabolic. but what type of fat is involved?

but what type of fat is involved? Who said a brown fat? Has anyone heard of brown as a question? Good. So we don't think of fat as being bad, but actually there is a type of fat or brown fat that is good for you. So the more of this brown fat you have, the more you expand calories because this type of fat is highly metabolically active and it's active metabolically, because it burns fat to produce heat. So we all know that person who is always opening the windows where everyone else is reaching for a jumper or bringing heating up. So these type of people probably have face lines high levels on which happens, partly because they're burning more calories because their brown fat is more active. And hence why they're generating more heat and they feel hot. So thermogenesis, insulation and storage of energy are important or fat or are important functions of fat.

What about defense against pathogenic organisms? Yeah, macrophages.

So macrophages are white blood cells and they are seen actually in one of the layers in the skin, one of the connected tissue layers in the skin. So I'll discuss a bit about loose connected tissue and part of the function of loose connected tissue underneath the skin is that it serves as the first line of defense actually against a potential pathogen.

So if you get a cut in your skin the white blood cells and the leukocytes which are there in this connected tissue layer underneath the epithelial layer of the skin will step into action and they will be the first line of defense at least in terms of the adaptive immune system. Tissue repair as well, so when we cut ourselves, we have scar tissue eventually being formed. And if actually if the cut is deep enough we know that that scar tissue is permanently there so there's no replacement with the original cells. And actually a scar is made up of phytocytes or fibroblasts which secreted the extracellular matrix proteins collagen.

So what a scar basically is is several names of collagen arranged in a sort of quite homogeneous pattern and so the reason why scar tissue gives you that appearance of being a scar tissue is that the rest of our skin the collagen fibers are arranged in a sort of a has it random way.

Whereas on scar tissue forms it's all uniform and that's why you can tell a scar from the surrounding tissue.

And scar tissue is connected tissue.

So various functions depending on the connected tissue type and the location in the body as well. So quite a varied array of functions.

So as said before what separates connected tissue from other tissue types is that it contains extracellular matrix.

It produces extracellular matrix and secretes it and so the tissue doesn't just consist of cells it consists of this other stuff and so the extracellular matrix consists of three different types of fibers.

So there are collagalous fibers, elastic fibers and reticular fibers and they different their relative composition of the different extracellular matrix proteins.

So the extracellular matrix proteins are elastin, bryphonin and collagen. So elastin is produced and secreted by fibroblasts but also smooth muscle cells within the arteries.

As its name suggests it's highly elastic and very durable and constrict, so vasodilation, vasoconstriction.

But if they're not supported by connective tissue, they can dilate too much or constrict too much, there's no support. And so over time, if you lack this connective tissue support in the arteries, then what happens is the arteries weaken over time. And there is a condition which we'll discuss later on, which is brought on by a lack of fibrin actually.

And fibrin supports elastin in an active tissue. So fibrin and elastin work together in elastic fibers and so the function of elastin is much weaker if fibrin is not present. So fibrin is a supportive glycopoietic which offers supports elastin within elastic fibers. And then there's collagen. So collagen is the main type of extracellular matrix protein. This is the most common extracellular matrix protein and it's produced and secreted by fibroblasts but also by chondroblasts and osteoblasts in the cartilage and bone respectively. And so I'll talk a little bit about that later on.

But then there are different types of collagen.

Collagen is the main the main extracellular matrix protein but there are different types of collagen and depending on where they're located and their role they can they can be broken down into these different categories. So collagen type 1 is found in maybe actually in tendons and ligaments and so densely packed, densely arranged fibers and the main function of collagen type 1 is resistance to tension.

In cartilage collagen type 2 predominates, so collagen type 2 is the main collagen type in cartilage and its role here is resistance to intermittent pressure and so cartilage coats the end of the long bones and it functions to reduce pressure on the long bones.

So essentially it makes them more durable. Collagen type 3 is evident in the smooth muscle but also the arteries and is present in particular skeleton around the major organs.

So if you ever do dissections and you remove a major organ, what you'll see is that coating each of the organs, so for the kidney for example, you have a very thin membranous layer and if you only can feel that, that you get into the actual kidney epithelium and so each of the organs has this particular lattice essentially and collagen type 3 is important for that and that functions in structural maintenance in expansible organs. So, out of the heart there's something called the pericardium so when you look at the heart what you're is the pericardium. So you can't actually see the myocardium which is the layer of the heart muscle, the outer layer of the heart. What you can see is the connective tissue which surrounds them, that's known as the pericardium.

And then finally collagen type 4 is found predominantly in the skin supporting the basement membrane as well as applying nutrients to the underlying epithelium and its role there is support and filtration so you don't necessarily need to know this but just so you're aware there's different types of collagen so it's not simply collagen and that's it there are different types of collagen and there are subtle differences in the properties of these different forms of collagen which are important because they serve a particular function. So fibroblasts are the most common type of cell found in connective tissue and fibroblasts are responsible for the synthesis, maintenance and turnover of the extracellular matrix.

So fibroblasts secrete the fibres, the ground substance and the interstitial fluid and this is what they look like. So they've got a characteristic branched and elongated shape but they perform quite a diverse array of functions so they also have new healing functions as I said fibroblasts are important for the formation of scar tissue and also they have some signaling properties.

Some immature fibroblasts can actually differentiate into other tissue types so they're blast can differentiate into fat, bone and cartilage.

So quite unique properties then.

So these are the categories of connective tissue. So there's connective tissue proper, there's cartilage, bone and blood. So I'm not going to talk about blood today. What I'm going to talk to you about is connective tissue proper, cartilage bone and connective tissue proper can be further subdivided into loose and dense connective tissue.

So this is an example of loose connective tissue and this is an example of dense connective tissue. So dense connective tissue has more fibers less space between the fibers as you can see there whereas loose connective tissue has quite a lot of space in between fibers and you've got a different array of fibres as well. So as you can see there you've got reticular fibres, collagen fibres and elastic fibres. Whereas in dense connective tissue you generally got one type of fibre and it's usually either collagen or elastic but collagen is the main one. As you can see from this picture here of the loose connective tissue.

You sometimes have different types of fibres together in the same structure, in the same location and that's important to remember that often the different connective tissue types function together and they work together to carry out the overall overriding function of the connective Loose-connected tissue underneath the skin, that's a good example of it, and it's called areola tissue. And this is an example of tendon. So loose-connected tissue can be further subdivided into three different types. And as you'll see from this talk, there's usually three of everything. So there's three categories of loose-connected tissue, there'll be three categories of dense, so everything's nicely divided into three different categories. So areola tissue again so supports the epithelial lining of not only the skin but also the GI and respiratory tract and the urinary tract.

Loosely arranged hence why it's called loose connective tissue. There's a lot of space between the fibers for the interstitial fluid and that's useful if you're functioning to cushion and provide some resistance to the underlying tissues, so it's supportive.

Adipose tissue has a similar function, so it's protective and it provides some much needed energy so bone marrow for example has a lot of fat inside the marrow or inside the bone there's a lot of fat and that actually can be tapped into for provision of energy when energy stores are low so wherever there's adipose tissue you've got a good supply of energy to the nearby cells and the nearby tissues but also fat is protective as well so underneath our patella there's a layer of fat there's a fat pad there and that provides some cushioning. Also around the kidneys there's what's known as perigrenal fat that again provides some cushioning from force being applied to the kidney so there's some protective qualities as well in fact not just the energy storage and insulation. and the structural adipose tissue is well suited to the function. So what you see here is essentially large adipocytes which contain a single lipid droplet and this droplet is arranged in what's known as a unilocular fashion.

It stores lipids in a single drop because brown adipose tissue stores lipids in multiple droplets and that's called multilopular and so what you'll find is that multilopular lipid appearance is great for breaking down fat because it increases the surface area for hydrolysis of the fat. It's the same as putting a potato into a pan, boiling.

Well if you cut it up, it increases the surface area, it's So that's the rationale behind why brown patch stores lipids in a multi-locular fashion, whereas white patch stores lipids in a uni-locular fashion, because as I said before, the purpose of brown patch is to utilise lipids, to burn patch and produce heat, whereas the primary role of that white elephant tissue is to store energy. And then finally, we have reticular tissue composed mainly of reticular fibres. So the fibres form very thin branching structures and these hold tissue together. I mentioned a soft skeleton, so the soft skeleton which surrounds most of the organs is made up of reticular tissue and here you have reticular fibres but also type 3 collagen, if you remember. and then you have dense connective tissue so this is further divided into three different types.

So you have dense regular connective tissue, dense irregular connective tissue and elastic tissue.

Dense regular is the most common type of dense connective tissue so this is the connective tissue found in the ligaments and the tendons and this is what it looks like under a microsurface histologically and the role of the tendons is to connect muscle to bone whereas the role of the ligaments is to connect bone to bone so slightly different function but of course they both are concerned with structural and mechanical support in the joint region.

Then you have dense irregular and it's called irregular because it's arranged in these irregular patterns.

So they're not nice sort of straight lines as you see with dead, regular. Sort of arranged more hazards. So the fibres are arranged in a haphazard manner. So you've got non-parallel fibres consisting mainly of collagen and this is found underneath the skin on the side because of the digestive. So imagine that you've got a layer of loose areola connected tissue in the skin, but you've also got dense irregular. So here is a good example of in the skin, you've got various different types of connected tissue and below that you've obviously got such a famous fat, so in fact you've got three different types. So the skin is a good example of various different connected tissue types functioning together.

And finally we have elastic tissue. It looks a bit like dense regular.

So the fibres are arranged in quite a uniform pattern but the main difference is that here you've got elastic fibres whereas in dense regular you've got collagen fibres.

And elastic fibres are found in the arteries as I mentioned, so they support the muscles in the arteries that are involved in vasodilation and vasoconstriction, but also they're found in the vertebrae, in between, well, in between the vertebrae actually, so they provide an important role in detection from force and stress that you will obviously encounter just walking in everyday light the amount of stress you put on the vertical column is very high and so if you live for 80 years that's a lot of where potentially you're putting on the on the vertical column.

Without connective tissue the vertical column will be degraded the bones and the vertical column will create decay quite rapidly because the amount of force and stress being applied to.

So tendons, tendons consist of dense regular connective tissue, closely packed collagen fibers and as I said they connect muscle to bone and the largest tendon in our body is the Achilles tendon.

So not only is it involved in mechanical support but it's also involved in sprinting.

So when you to move quickly. What happens is the Achilles tendon acts as a spring so it allows you to exert a lot of force in a short space of time and in fact in these sprinters have very short Achilles tendon whereas marathon runners have the opposite they have long Achilles tendons and actually long Achilles tendons are important for endurance running so that makes sense. we evolved two million years ago a hominin called homo erectus and homo erectus was a highly efficient effective enduris runner so our ancestors before this were not very good at running so we were we were originally tree-dwelling primates but two million years ago our anatomy checked because climate was changing we needed to move away from the trees. There weren't many trees, forests were deteriorating so it made sense that we evolved efficient means of walking around and actually we evolved to be long-distance walkers and long-distance runters and so the tendon is part of the reason why we have become quite a successful species actually. So the Achilles tendon attaches the calf muscle to the heel bone.

The problem with tendons and ligaments actually is that they, while being strong, once they do rupture or tear, you've got a major, major problem. And the reason for that is that the Achilles tendon, like other tendons have very poor blood supply and very poor nerve supply.

That makes them strong because muscles are susceptible to tearing.

Muscles are susceptible to damage and it's partly because they've got a large capillary supply. So if you look at a muscle tissue under a microscope you lots of tiny propellants. That's great for supplying nutrients, great for supplying cells which can help with tissue injury and repair, but not so great in the sense that it provides a weakness to the muscle. On the flip side of that, a muscle injury heals very quickly because of that to that tissue and you're able to then heal that tissue very effectively. David Beckham, he must have been about 20 years ago, he missed the World Cup because of a tendon rupture and you can see it's completely severed there, so a horrendous injury and you always need surgical intervention.

A tendon rupture cannot heal by itself.

A small tear in the tendon, tendon, you might be able to get some, a decent level of healing. But the problem with the tendon is that even if it heals, it doesn't feel as effectively as it once was.

And so the underlying function of that tendon is gone.

So you've lost some functionality of the original tendon. And what does that mean? You're more prone to further injury.

And that's ligaments.

There's a high probability that they'll need further surgeries on the same ligament in future and so that is part of the problem with tendons and ligaments are the same.

So ligaments connect bone to bone. So these are dense regular, they can also be dense elastic tissue and of course they to mechanically reinforce and strengthen the joints. They increase structural support and flexibility, but the main difference between the ligaments and the tendons is that ligaments ensure that there's no hyperflexibility. You don't want to overflex because that's where you could do damage to the muscles and the joint can become unstable. So the tendons are more concerned with you to move effectively and move efficiently whereas the ligaments are more concerned with preventing you from overdoing it essentially. But similar to tendons the ligament injury necessitates a lump eating process often results in scar tissue that weakens the ligament and then it's obviously not as well able to carry out its original function of support and that's where you see in elite athletes, so I'm using elite athletes here as a good example, a tissue that's very good at carrying out its function of structural support, mechanical support but in certain walks of life we push that to the limit and elite sport is a good example of that and not only do they do things where it's not humanly possible to sustain a particular action but it's also not medically advisable to sustain those actions for an extended period of time, which is why the sharp life of an elite athlete is very low and so the main reason why most of them are retired by the time they get into their mid-hurt is because the wear and tear and the pressure of the joints and the connective and so a crucial injury in sport is the anterior cruciate ligament injury and so this is the anatomy of the knee joint and you have connecting the femur to the tibae you have two ligaments so one in the front which is called the anterior cruciate ligament and one at the back which is called a posterior of crucial ligament and they crisscross each other like this and the anterior ligament helps you to move your knee in that motion but both of these ligaments ensure that you don't overdo it. Of course you don't want to flex your knee beyond you know beyond that that would be dangerous to the to the joint it will make the joint unstable and you'll get injuries of the surrounding tissue as well. So the function of the ligaments are to hold things in place and ensure that there isn't an overflexing. And then you have the lateral ligaments on one side and these, if you feel your knee joint now, you can feel on running down either side of your knee joint you have these very durable very hard ligaments and they ensure that your leg doesn't actually rotate. So the two leg bones don't rotate independently of each other. That could be catastrophic. So the whole point of the ligaments in the context of the knee joint are to provide stability and to ensure that there isn't an over flexion of the muscles. And so essentially that you don't move your knee in places where you shouldn't Yannick Sinner won his first grand slam and Novak Djokovic was unable to defend his Australian Open title.

Now when I first gave this lecture about 10 years ago there were two tennis players who were regarded as the greatest male tennis players of all time and so these were the rap on Nadal and Roger Federer.

They were playing, actually Nadal is still not retired, but obviously Roger Federer has retired.

Novak Djokovic is still playing and he obviously is regarded by some to be the greatest tennis player all the time.

But when the last chapter is written on who the greatest player is, it could very well be who was able to stay injury free for longer. So what people measure greatness in terms of tennis on is the amount of grand slam of major titles like that. So he's got I don't know 20 or so Nadal's got 22, Djokovic is on 24 but actually Beru has been quite lucky because Nadal has missed at least eight or nine major tournaments due to And what we know about Nadal and his style of play and the things he does with his joints, you know, he wasn't going to survive for long, playing under those sorts of conditions. The amount of strength he puts on his joints, what you've got is extreme rotational forces going across the knee. So he plays a double handed backhand, a lot of forces, a big man, strong guy. there's a lot of force going through that knee joint at that particular time. While the Federalist plays a single hand with that hand, he doesn't actually have that much rotational force going across his knee joint. That may have been one reason why he was able to stay an injury free for most of his career. Ironically he did actually retire due to a knee injury but it took him a long time before he succumbed to the injury. He was on the dial side, continual injuries. He's had an anterior cruciate ligament surgery and various other surgeries to his joints. And so part of that is the amount of strain he puts on his body. And in elite sport, you are forced to do things that the human body was simply not designed to do. And so while our connective tissue, our ligaments, our tenders do a very good job, they do a very good job under the situation and circumstances which they evolved to do that in but we were not evolved to be elite athletes putting our bodies through this sort of thing and that is why you commonly see very profound injuries in elite athletes but you rarely see that outside of elite athletes.

Of course recreational sport just put strain on your body particularly if you do it frequently and over a long period of time. You do get wear and tear injuries as well but it's fair to say not to the same extent as you would encounter in elite sport but then sometimes you have connective tissue injury or damage not brought about by injury as such not brought about by things you're doing to your body but also things that have been brought about due to genetics and Marfan syndrome is a good example of a connective tissue disorder due to keys.

So what this is, it's a mutation in a gene called fibrillin and remember I said fibrillin is an important extracellular matrix protein that supports elastic inelastic biomes.

So Marfan syndrome is an And patients have some unique characteristics, but they're able to pull their skin quite a way up than most people can. They've got quite a lot of flexibility in their skin, partly because they've got no elastic fibers underneath their skin. And remember I said that you've got elastic fibers just below the gluteal rheitis. And so if you don't have that, you're able to pull your skin quite a lot. people with Marfan syndrome have hyper flexibility of the joints because there isn't as much connective tissue in the joints that they're able to flex and over flex essentially. They've got a high heart balance, a high roof of the back. Now these particular symptoms or disease features are not lethal but one symptom of Marfan syndrome is lethal and that is when it affects the arteries and the So as I said, elastin and elastic fibers are important for providing support to arteries when they constrict and when they die a day. You don't have that. Over time, the arteries weaken, the artery walls weaken, and then you get what is known as aneurysm.

So the arteries enlarged.

Over time, enlarged arteries and weakening of the walls of the arteries can lead to a rupture of the anise and that is usually fatal. So when you get a rupture of the aorta then most people are dead within a few seconds. So it can be quite catastrophic and if you think about someone in their 20s they obviously don't have other respect is associated with heart so it was often misdiagnosed as something else this sort of condition and so the more we studied Markovian Syndrome the more you realize that you have to look at young people and look at genetic defects, particularly if you exhibit other symptoms and it's actually the symptoms associated with the cardiovascular system that are serious. And so the earlier you detect that, the better you're able to prevent yourself from reaching a level where you develop an aneurysm.

Also, elastic fibers are an important part of the valves of the heart. So the valves of the heart are not made up of heart cells or cardiomyocytes, they're made up of connective tissue cells. So the valves are made up of connective tissue. because of a mutated equilibrium, then you're also going to have a defect in the bars of the heart. And so because of this people develop some serious problems associated with cardiovascular disease that you wouldn't normally see in people without a classic respect for heart disease such as smoking, diabetes, obesity. So quite a profound disorder that has quite catastrophic consequences potentially. Then you have specialist connective tissue. Cartilage is a good example of that. And again, there are three types of cartilage. So there's three of them, but it's nice and easy to remember. So if you're over in a state where you're trying to remember their different types, just remember there's three of them. So at least you know how many you've got to remember. And so these are the three different types, hyaline cartilage or articular cartilage, elastic cartilage and fibro cartilage. And they're highly durable and elastic tissue. And this is an example of the function of hyaline cartilage. So it coats the end of the long bones. And one of the differences between the different types of cartilage, they differ slightly depending on the composition actually of the cartilage types.

Highline cartridges have a lot of chondrocytes. They've also got decent amount of collagen fibers but they've got a lot of ground substance. So they've got a lot of things like Agricam which provide this gelatinous sort of texture.

Here you've got elastic cartridge, they have a lot of chondrocytes as well.

Now fibrocartilage is similar to high-line cartilage but it has less of the ground substance, less of the gelatinous ground substance and more of the fibrous, more of the collagen fibrous. And as its name suggests, it's high fibrous.

So fibrocartilage, if you remember that it's more fibrous in nature than high-line cartilage.

So cartilage may make up the ear, the outer ear and the nose.

So both of these are made up of cartilage and the main cell type that predominates in cartilage are the chondroblasts.

So those are the active cells and the chondrocytes are the mature cells and once the chondroblasts is generally secreted, it's exercised in a matrix, it becomes a chondrocyte and effectively imprisons itself in what is known as a lacuna.

So effectively a black hole, it's like a space, and so it's so successful that it's rendered itself in active, essentially. It produces a lot of this stuff and then it's sort of a bit isolated and then it's technically inactive, although the caveat is that recent studies have shown that these chondrocytes in the lacuna might actually provide some signaling function.

So they might be able to function in the context of signaling to other cells and so they still might be able to do a role. So while we might have previously thought of them as being inactive, they could fulfill some role skill.

So I mentioned that the elastic carpet is found in the outer ear, similar to high line cartilage but there's more elastic fibers.

So actually the properties of all the different types of cartilage are very similar. There's only subtle differences between them.

So as well as the outer ears, also found in the epiglottis of the larynx, and then fibric cartilage, fibrous type of cartilage, and its role generally is to provide tensile support and resistance to pressure. So the primary function of all cartilage is actually resistance to intermittent pressure.

And as I mentioned before, in the spinal cord in the vertebral column you have a lot of pressure, a lot of force is acting on the spine.

So I mentioned we have elastic dense connective tissue in the vertebral column in between the vertebrae, but you also have fibrocartilage as well. So another example of two different types of connective tissue located together to carry out that function.

A unit type of fibroclastic is the labrum. So the labrum is balanced on the inner lining of the hip joint.

So this is the femur, the long bone here, and the end of the femur is coated with this high line cartilage, but the inner layer of the hip joint is coated by fibroclastic.

So slightly different properties to highlight more fibrous in nature more collagen actually Andy Murray has what's known as a label of tear so he had an injury which meant that there was constant pain constant inflammation and the reason for that is that you have this tear so your body's perceived that there's something that needs healing but unfortunately the legroom cannot heal by itself. So you will always have this wound in the labour. That means you're going to have constant pain for the rest of your life and there's no way you can get rid of it and it's quite intense pain for those who suffer from that.

Surgery is not recommended either unless you're an elite athlete and Andy Murray had the labour taken out but that means that the joint joint is more susceptible to further injury because you're not protecting the inner layer of the hip joint.

The joint doesn't move as effectively and essentially what happened was that you had to have metal pins that kept the femur into the joint and of course that joint isn't going to be able to move as effectively after you've stuck the metal pin in to keep the the upper leg bone in place and it's likely that Andy Murray's career is not exactly going to improve after this and so he is still playing he actually played yesterday and he played with the Australian Open but he's obviously not going to reach the levels he was able to reach before. He's doing all right but still clearly this injury has had a major impact on on his ability and so it's not recommended to perform surgery unless you're an elite sport and actually there's There's no evidence that the surgery is beneficial in terms of the chronic pain. So people who have the surgery complain still that there's pain in the area and the joint is basically not as flexible and so you're also susceptible to further injury. So on the balance of the pros and cons, surgery is a bit iffy and so this is a good example again of ligaments tendons as well as cartilage not being able to heal very effectively and part of the reason why they have this ability to provide structural and mechanical support means that they're also susceptible if there is an injury so they're not as able to repair the damaged tissue.

But one connected tissue type that is able to repair itself very effectively, very efficiently is bone.

So bone of course is a rigid structure, it's the main component of the skeleton and the main function is protected and supported.

But bone is unique because it also provides the red blood cells and the white blood cells in the marrow. The bone is made up of cells, organic matter, such as the collagen, but also inorganic matter, and that is what sets it apart from other types of connectivity. So it's made up of what we call hydroxyapatite, and that is calcium phosphate.

Now there are different tissue types within the bone, so osteoblasts, osteoclasts. Osteoblasts produce the osteoid or the extracellular matrix of the bone and osteoclasts are responsible for resorption of bone or bone turnover.

Osteocytes are osteoblasts which are essentially inactive, a bit like the chondrocytes in the cartilage but actually chondrocytes play a function in bones as well and I'll come onto that in a sec.

So the endosteum, so the endosteum is the inner lining of the long bone here of the diabetes sharp and that is a connective tissue type as well so it lines the inside of all the long bones now there's also the periostem here and that is a connective tissue a thin connective tissue that surrounds the bone and when you get a fracture when you injure your bone the reason why you feel pain is that that thin layer is heavily innervated, a lot of nerves and a copious blood supply. Aside from that you don't have much innovation in the bone. So the reason why you feel pain when you break the bone is because of that fractured bone putting pressure on the periostin. So there are two main types of bone, there's compact bone or cortical bone and spongy or trabecular bone.

So cortical bone is found in the diaphysis, so the main shaft of the bone you can see that here, whereas spongy bone or trabecular bone is found in the metaphesis and the epiphesis, so the ends of the bone. As you can see, the compact bone is more dense, whereas spongy bone is less dense.

And then bone marrow, as I said, so bone marrow, this is what bone marrow looks like in an interventional chart, so lots of blood cells, lots of red blood cells, lots of megaterreocytes, lots of white blood cells. But as we get older, our bone marrow occurs from being a nice red-pink colour to becoming a yellow colour, and that is because you've got more adipocytes, more fat cells in the bone marrow than you do other cells have. some of you might like to eat bone marrow and the reason why you like to eat it is because it's nice and fatty and so a lot of fat in the bone marrow. Now people who are pro-geosipirosis for some reason they have a predomination or they're an abundance of this adipose tissue the adipocytes in the bone marrow versus other cell types.

So bone enjoyment, so you're going to do a blackboard test on bone, so pay attention. A few people are sitting straight enough and so pay attention to this, this is going to be on your blackboard test.

this is going to be on your blackboard test. What is that E represent here? E, what is that E represent?

represent? The epithelial growth plate and that is the main site for new bone formation, so that is critical.

So this growth plate is the site of new bone formation and new bone is formed on the basis of cartilage actually.

So first cartilage forms at the site of new bone formation, then it's taken up, it's resorbed and bone is formed on top of it.

So bone is formed from cartilage and you can see a nice lattice texture here of the spongiotrabecular bone and this is compact bone found in the shaft of the long bones.

You've also got cartilage here of course, the highline cartilage, so it coats the end of the long bones and these are the So effectively the bone forms from here outwards, so this is how the bone extends lengthwise.

So what happens first is, what happens first is the, what's known as the reserves. So what you've got here is chondrocytes, they're simply not doing much, they're hanging out, they're really not involved in anything, they're just there.

So that's called the reserve zone. And then what happens is they're stimulating to proliferate by various stimuli.

For example, growth hormone stimulates chondrocytes interaction, they proliferate.

So they undergo proliferation, mitosis, cell division.

So you then suddenly got more chondrocytes. And then what happens is these chondrocytes, these cartilage cells, they hypertrophy they get larger they start to secrete produce things and secrete things such as extracellular matrix proteins proteoglycans etc as well as calcium and basically what now is a lengthening of the bone because of this all of these three processes it's not called bone yet still cartridge so these are the chondrocytes that have secreted extracellular matrix as well as but they don't have the properties of bone quite yet and then what happens is that these cells start to die so you get apoptosis of the chondrocytes they start to die and once that happens you have infiltration of the capillaries.

Capillaries supply osteoprogenitor cells into the air So, that is when you have osteoblasts and osteoclasts infiltrating this area of calcified conga-susps, and the osteoclasts resorb that calcium, they break it down, and the osteoblasts secrete the osteode, the heterocellular matrix of bone, and once that osteode is formed, you subsequently get mineral formation so you get mineralisation so you get calcium and phosphate laid down and so you can clearly see that in order for bone to lengthen for bone to form calcium I'm sorry chondrocytes cartilage cells have to do their job so new bone is formed thanks largely to to cartilage. Now this only happens of course if your bones are still growing. Some of you will still have bones that are growing and the epithelial plate has not reached completion.

Some of you might have stopped growing which means that this process won't be happening but the bone still undergoes turnover so into late adult.

So you've still got osteoclasts that break down bone that needs to be repaired, that breaks down older bone and you still have osteoblasts that secrete new osteoid or the formation of new bone. So it doesn't happen in this manner but you still have an isolated example of turnover where you've got old bone or injured bone being replaced by new bone and that happens throughout your life.

So it's important to remember that osteoclasts are involved in bone resorption, osteoblasts are important for the opposite which is the production of new osteoid, new bone essentially and the bone extracellular matrix as we know consists of a lot of calcium and a lot of phosphate as well as the organic compounds so collagen and the ground substance and in fact bone accounts for 99% of our total body storage of calcium so highly important reserves of calcium thanks to the bone and it's actually the mineral deposit calcium phosphate which provide bone which are for bone the rigidity and the strength needs to carry out its main function of protection and support and compressive strength is what gives bone its unique properties and that is predominantly brought about by calcium and phosphate.

So histologically this is what the extracellular matrix looks like of the bone. So I mentioned the calcium and the phosphate but initially in the osteoid you've got ground substance as well as the collagen. Osteoclasts are multinucleated in their large cells so you can easily tell them apart from other cells within the bone.

As we saw with the cartilage here you've osteocytes enclosed in a lacuna and so this is inactive as well but again with a caveat that it could still function to signal to other cells. It no longer produces the osteoid though so osteocytes no longer produce osteoid they're no longer capable of producing more extracellular matrix proteins. So osteoblasts are located immediately above the osteoid which is newly formed bone extracellular matrix.

So this is a disorder called rickets and rickets is brought about because of vitamin D deficiency.

Now we never used to see a lot of cases of rickets but because of the cost of Victorian era diseases manifested today. We see scurvy and we see ricketts and scurvy is born by a lack of vitamin C, so vitamin C deficiency. Fruits and vegetables are very expensive these days. Many people can't afford to buy a lot of fruits and vegetables for their families. And that can mean sometimes children develop vitamin C deficiency. Vitamin D deficiency is actually becoming more and more common as well because of the cost of living classes and the problem with vitamin D is actually we can produce quite a lot of vitamin D without the need to have a diet but that's only if you're fair skinned and you're out in the sun a lot.

So fair skin actually evolved in order to produce vitamin So, as we migrated out of Africa, we started to inhabit northern attitudes, such as ureins. We no longer needed to protect our skin from the damaging effects of UV radiation. But the skin is important for production of vitamin D, because when exposed to solar radiation, vitamin D is produced in our skin cells. and so fair skin evolved to allow this to happen because if you've got dark skin and you're living in Europe in the winter you're not going to get enough sun to produce enough vitamin D yet.

Now the problem is we see an increased amount of rickets in people of dark skin living in Europe and that is compounded by the cost of living prices in the last couple of years. Thankfully vitamin D can easily be treated actually with or vitamin D deficiency can be treated easily with vitamin D supplementation.

It's very difficult to get in our diet naturally so it's not found in many food sources so highly prevalent in oily fish but as we know with oily fish such as salmon and mackerel that's not very cheap so that's part of the problem with an increase in rickets in recent years.

So vitamin D is important for calcium absorption.

For calcium absorption to happen vitamin D is supported and so without vitamin D you have much less calcium absorption and that is the reason why rickets is associated with people of dark skin living in northern attitudes.

Now a common bone disorder is osteoporosis and effectively what this is is bone weakening with age.

So bone density peaks in your 30s and then it gradually declines thereafter but there's a much bigger decline in females after the menopause than in males and the reason for that is that estrogen is also important for calcium production and estrogen is an important signaling factor for osteoblasts.

So if you have suddenly have less estrogen your bone turn over favors resorption rather than production of new osteoid, production of new bone. So that is why women after the age of menopause tend to have be more susceptible to osteoporosis. So it's very very common in elderly patients and that is because over time your bones simply weaken and essentially this is due to an imbalance in turnover favoring resorption and as I said before people with osteoporosis tend to have more bone marrow fat than they do other cells within the bone marrow and this increased level of fat inside the bone marrow is highly correlated with risk of osteoporosis.

So there are things we can't do about it, age, gender, the metaphors, relative factors, so some genetic variants, some mutations are associated with an increased risk of osteoporosis and there are other disorders which are inherited or caused by mutations in our genes.

But there are modifiable factors.

Alcoholism is highly correlated with increased risk of osteoporosis.

I mentioned a bit of D, deficiency, smoking, poor diet, some medication such as medication for gastric reflux are also associated with osteoporosis which is why it's not a good idea if it takes some forms of medication chronically over longer the time so there's a balance between protecting yourself from the discomfort of reflux but also preventing yourself from increasing your risk of conditions such as this. Over training as well so people who do a lot of running tend to be more prone to osteoporosis so your bones weaken over time. And endurance running has been linked to decreased risk of osteoporosis, but weight training appears to have the opposite link. So weight training appears to be protective and it increases bone mineral density into old age. So it's recommended that you do both cardiovascular training as well as resistance training in order to preserve your health into into middle-age and beyond.

Some people expose to heavy metal and that's usually because of an occupational hazard, are also prone to bone disorders such as osteoporosis.

That's obviously quite rare and isolated.

So when you get osteoporosis you're more prone to fractures and so the risk of fracture increases dramatically if you have osteoporosis and where are you likely to develop fractures? The places we commonly see fractures are the thoracic spine so the spine in the thoracic region and it starts off with quite small fractures, hair-like fractures, which over time increase and expand and they gradually affect the spinal cord so the nerves and when this happens you basically get a lot of not only weakening of the vertical column but you also get some form of loss of pain as well. To some extent this sort of damage to the nerves prevents you from experiencing pain and so that in elderly people it's And because it happens so gradually, so a small amount of increase in these tiny hairline factors over a long period of time, that's where you get a gradual sort of hunching that we associate with the whole thing.

Another place you commonly see factors associated with osteoporosis is in the wrist.

See the radius here, there's a fracture there and of course when you get a fracture in the wrist, that's where you're unable to be completely independent, that's when you need more assistance and more help so it can greatly affect quality of life for patients who have fractures associated with the wrist.

But what really increases your mortality rate when you have osteoporosis and when you have fractures associated with osteoporosis is when you get a fracture in the hip. So this is where it becomes a life threatening. About 20% or more of patients who have, of elderly patients who have hip fractures, 20% or more die within a year or so of that injury. And there's multiple reasons that could account for that.

Of course it's debilitating, if you lose the joint there, you're not going to be as mobile, you're likely to be bed-bout for a substantial amount of time in your recovery, that can lead to blood clots, that can also lead to mental health problems, someone who's potentially gone from being completely independent to being dependent and being bed bound, being in a wheelchair, it's going to affect their mental state that could then compound the problem with physical injury. But this is a major injury in announcing being patient. There's a lot of information, a lot of inflammatory cells, immune cells infiltrating the area that can put pressure on the body as a whole. So all of these factors add up to greatly increase your risk of dying if you have this fracture as an elderly person.

And this is the site we commonly see hip fractures.

So it's known as the femoral neck. So it's the neck of the femur. And that is because the neck of the femur is actually its weakest point. So that is where you commonly see practice in the altebitum patients. If you remember that's made up of spongy bone or trabecular bone, so it's not compact bone. So of course it's weaker in that regard, but then if you then factor in the fact that it's weaker because of osteoporosis and because simply of aging as well, that means you've got a very weak bone. So it's highly susceptible world to practice.

That's why when elderly people fall it's almost always a serious matter because of the risk of practice even in an elderly person without osteoporosis. The good thing is we've got a good way to diagnose osteoporosis so we use DEXA scans.

Essentially energy beams, low dose x-rays are targeted at the bones and what's measured is the absorbance of this energy in the bones. If you subtract the organic matter what you're left with is the mineral matter, so the calcium phosphate.

And so you can calculate how strong this calcium phosphate is, how strong the mineralization is and that's what's refer to as bone mineral density. And so what the indexer gives you is a score, so unambiguous, a nice clear-cut diagnostic test. If you score between plus one and minus one, you're in the normal range. If you score between minus one and minus 2.5, you're in the osteopenic range.

So osteopenia is bone weakening, commonly associated with aging, but it doesn't quite reach the threshold of osteoporosis. But of course it is a precursor to osteoporosis, so people still need to be careful and try and change their lifestyle if they develop osteopaedia. And then if you're in the range of minus 2.5 to minus 4, that's osteoporosis, so significantly below the normal.

And as I said before, hip fractures in high lethality and high degree of immobility as well caused by that injury. So it's unlikely that someone who sustained an injury like this when they're elderly will be able to be as mobile as they were before. So connective tissues have diverse structures and functions depending on their anatomical location.

They also have a commonality in their structures and and cushioning.

So mechanical support and compressive support. The extracellular matrix is unique to connective tissue and the composition of the extracellular matrix varies between the different types of connective tissue. But we aren't finished guys, we aren't finished. If you're making your way out please be quiet.

The extracellular matrix consists of extracellular matrix proteins, ground substance and interstitial fluids. The bone extracellular matrix contains mineral salts for hardness and rigidity and actually that's what sets bone apart from other connective tissue types is the ability to synthesize and lay down mineral salts in the form of calcium and phosphate.

Bone and adipose tissue are unique among connective tissue both in their structure and their function and so this is going to be the focus of the Blackboard test. So look into bone disorders and the composition of bone as well as adipose tissue structure and A