Development of the Limb Bones

00:01 We´re now going to discuss the limb bones and how they form at the core of the developing limb bud.

00:06 Initially, the limb bud is coming from the lateral plate mesoderm.

00:10 It´s covered by ectoderm and has a core of mesenchyme.

00:14 Mesenchyme is undifferentiated tissue and at the very core of the limb bud will be some denser condensed mesenchyme.

00:22 Now, I want you to note at the very tip, we have the apical epidermal ridge.

00:26 That´s gonna be very important when we talk about the genetic signals that cause limb bud growth.

00:31 But right now, we´re gonna concentrate on that condensed mesenchyme.

00:35 As the limb bud extends, that condensed mesenchyme will start to form models of the bone which will transition to cartilage models of the same bones and after a while, we have a rough model of the humerus, the ulna, the radius, and all the carpal bones, metacarpals and phalanges in the upper limb segment.

00:56 Correspondingly, in the lower limb, we´d have models of the femur, the tibia, the fibula and so forth.

01:01 Now, these cartilage models take on the appearance of the regular bone but not exactly and as we extend, we can start to see roughly all the bones of the upper limb present in a cartilage mode but the process of transitioning from this mesenchyme, to cartilage, to bone is an important process called endochondral ossification.

01:24 So let´s discuss how that occurs.

01:26 Initially, the mesenchyme is loose undifferentiated connective tissue replaced by cartilage.

01:32 Cartilage is a bit tougher than mesenchyme and can put up with a lot more stress but it´s not strong enough for the demands that we´re going to place on our body.

01:41 So we need to replace it with bone.

01:43 Another important thing about cartilage is that it´s avascular.

01:46 It doesn´t have any blood vessels within it and it relies on diffusion to get nutrients to and from those cells, the chondrocytes and chondroblasts within it.

01:55 The first step in ossification in this process is going to be that an artery grows into the cartilage model and brings osteoprogenitor cells with it.

02:06 Cells that will form bone.

02:08 This is gonna create what´s called a primary center of ossification and in a long bone such as the humerus, we´re going to have that artery grow into the shaft of the bone, bring those osteoprogenitor cells in and create a primary center of ossification where the bone starts to replace the cartilage.

02:27 Now, one thing that happens in this process if we have a subperiosteal cholera bone form around the shaft as well.

02:34 So we have some relatively dense bone forming around the shaft but the primary center of ossification is deep within it and it begins replacing cartilage.

02:44 The same process occurs on the ends of the bones as arteries grow in there creating secondary centers of ossification.

02:52 This is going to leave cartilage between the primary center and the secondary center which are replacing that cartilage with bone.

03:01 Now, if this happened quickly, our bones would never get any larger than that cartilage model.

03:07 But thankfully, the cartilage is proliferating and creating daughter cells and it winds up effectively pushing the primary center and secondary centers of ossification away from each other.

03:18 That is gonna be called the epiphyseal growth plate and the term for the segment of bone with the secondary center of ossification is an epiphyses, the term for the area with the primary center of ossification is the diaphysis.

03:34 And there´s an area in between the two on the diaphysis side called the metaphyses.

03:38 Now, as those primary and secondary centers of ossification get closer and closer, the epiphyseal growth plate is trying like mad to proliferate and push them away from each other and it´s not until our teens or even early 20´s that all the growth plates in our body close.

03:58 Once the primary and secondary centers of ossification meet, the bone has reached its final mature size and it can no longer elongate and that´s what determines how tall we are, how long our limbs are, and so forth.

04:12 So once those growth plates close, the remnant of the epiphyses and diaphysis meeting is called the epiphyseal plate or growth line.

04:22 And so, at that point, the arteries that supplied the primary and secondary centers of ossification are now nutrient arteries that provide blood to the bone and the veins that are corresponding with them carry blood away from the bone.

04:36 The core of the diaphysis is relatively hollow and that´s gonna become the medullary cavity and it´s an important site for blood formation.

04:45 So hematopoiesis is occurring in there even though it shifts to other bones over life.

04:50 Initially, the long bones are a major site for blood formation.

04:55 Now, in the process, we don´t just have a solid core of bone throughout our entire limb.

05:03 We need to have joints that allow movement to occur between those bones.

05:06 This happens because the mesenchyme that´s in between the bones that are forming does not form cartilage but it stays as somewhat loose or probably dense irregular connective tissue.

05:20 And as the bones form, that connective tissue starts to become hallow and we have synovial spaces forming within in.

05:29 Now, synovial fluid is the fluid that allows bones to glide across each other without too much friction and it´s very rich in hyaluronan which is going to be found in these developing spaces.

05:39 By the time bones have completely formed, we have synovial space with a fibrous joint capsule around it.

05:48 We have hyaline cartilage on the side of each bone that´s connecting at the synovial joint.

05:54 And if we have any intra capsular ligaments like the anterior cruciate ligament or the posterior cruciate ligament, they´re gonna form as remnants of that connective tissue that is initially found between the developing bones.

06:07 Except they´re gonna become very dense and regular with definitive fiber directions so that they can help keep the joints together.

06:14 Now, things that can go wrong in this process include achondroplasia.

06:19 Achondroplasia is a mutation of the FGFR3 gene and its corresponding protein.

06:26 The fibroblast growth factor receptor 3 is involved in several things but one thing it´s involved in is elongation of the cartilage growth plates.

06:36 Achondroplasia is a genetic condition that is caused by a mutation in the F G F R 3 protein. Now, this protein has a negative effect on the growth of the cartilage phase in the endochondral ossification process.

06:52 A mutation in this receptor results in overactivity of the receptor signaling pathway, which impairs the growth of the cartilage template or model of the long bones. This is caused by impaired growth and proliferation of the chondrocytes.

07:07 And people with achondroplasia tend to have no real defects of intellect or development other than they just tend to be shortened because their limb bones and facial bones don´t tend to elongate to the same degree that they would if that mutation were not present.

07:28 Now, something that´s important to distinguish from achondroplasia and pseudoachondroplasia are what are known as little people.

07:34 These people don´t experience the pubertal growth spurt because they don´t have enough growth hormone present at that time and so, they´re normally proportioned.

07:43 They have typical limb segment length, they have typical facial length, they´re just smaller than what we would consider to be typical.

07:51 Now, if too little growth hormone can lead to someone being foreshortened, too much growth hormone during development can cause gigantism and in this case, the growth hormone creates an excessively active growth plate and people with gigantism get very tall, very large, and that´s going to be due to the growth hormone affecting the growth plate.

08:14 If we have a pituitary tumor that creates too much growth hormone after our growth plates have closed, the bones cannot elongate anymore.

08:23 So people note enlargement of other areas of their body such as their ears, their nose, and one thing that people will sometimes complain about that´s an early sign of acromegaly is that they keep having to buy bigger shoes because their feet, even though they shouldn´t be getting larger are.

08:39 Now, one important feature in closing growth plates is the amount of estrogen that a person in exposed to.

08:46 So for that reason, women who have more estrogen relative to the level of testosterone than men, tend to be shorter than men because that estrogen closes the growth plates sooner.

08:58 Now, please note that as a generality.

09:00 Women that tend to be shorter than men, however, the level of estrogen and testosterone is only one thing that´s leading to the closure of the growth plate.

09:08 Thank you very much and we´ll see you on the next talk.