V.C - J - Factors in Initiation of Ossification (intramembranous & endochondral); Role of Mechanobiology in Development

Question 1

What are the two different ways which bone is created during foetal development?

Answer 1

Intramembranous ossification and Endochrondral ossification - this is where bone originates from cartilage

Question 2

What is the definition of intramembranous ossification?

Answer 2

This is the immediate conversion of mesencyhmal cells to bone

Question 3

Where does intramembranous ossification primarily occur? There is an exception where intramembranous ossification also occurs, try and name this site?

Answer 3

Intramembranous ossifciation occurs primarily in the skull, including cranial suture lines The exception includes the periosteum surrounding the outer surface of long bones: its growth is also considered as intramembranous

Question 4

Intramembranous ossification occurs in 4 stages Describe stage 1?

Answer 4

Stage 1: Ossification centre formation The mesenchyme condense to form a membranous sheet permeated with blood capillarie The osteoprogenitor cells found here differentiate into osteoblasts and collagen fibres surround the cells

Question 5

What forms the osteoprogenitor stem cells found in the ossification centre of the connective tissue?

Answer 5

The osteoprogenitor cells arise from the mesenchumal cells differentiating

Question 6

Describe stage 2 of intramembranous ossification

Answer 6

Stage 2: Calcification The osteoblasts secrete osteoid and some are enveloped in intracellular matrix forming lacunae and converted into osteocytes The osteoid calcifies to form spicules of bone

Question 7

Describe stage 3 of intramembranous ossification

Answer 7

Stage 3: Trabecular and Periosteum formation The remainder of cells synthesise and secrete osteoid, then calcify to become woven bone trabeculae Cancellous bone forms from interconnecting network of trabecualae, including spaces for separating - form red bone marrow Vascularised membranous sheet condenses to become perisoteum

Question 8

Describe stage 4 of intramembranous ossification?

Answer 8

Stage 4: Periosteum Development The periosteum, which contains osteoblasts, constructs a woven bone layer just deep to its surface which later becomes lamellar bone forming the outer compact layer of bone (the cortical bone)

Question 9

Describe the stages of intramembranous ossification

Answer 9

https://s3.amazonaws.com/classconnection/403/flashcards/11907403/png/ppngjpgpngjpg-16814C707DF6C6A5657.png

Question 10

We have now discussed intramembranous ossification (Ossficiation centre formation, calcification, trabecular and periosteum formation, periosteum development) We will now discuss endochondral ossification Define both intramembranous and endochondral ossifcation?

Answer 10

Intramembranous ossifcation - the immediate conversion of mesenchymal cells to osteoblasts - occurs primarily in the skull, including cranial suture lines Endochondral ossification - the process involves cartilage - the conversion of mesenchymal cells to chondroblasts producing the cartilaginous template and then the mineralised mode is replaced by bone

Question 11

What is the main mode of ossification within the centra of the vertebrae?

Answer 11

Endochndral ossification is the main mode of ossification within the centra of the vertebrae

Question 12

Which type of cartilage is most likely to ossify to become bone? Hyaline Fibrous Elastic

Answer 12

Hyaline cartilage is the most likely to ossify to become bone

Question 13

Before step 1 of endochondral ossification begins where the hyaline cartilage model is formed, describe how the foetal hyaline cartilage model is formed? (from mesenchymal stem cells to hypertrophic chondrocytes)

Answer 13

https://s3.amazonaws.com/classconnection/403/flashcards/11907403/png/ppngjpgpngjpgpngjpg-1682A41E7512C6F54BD.png

Question 14

Hypertrophy and division of chondrocytes occurs, hyaline model begins to calcify. As calcification progresses, diffusion of nutrients through calcified matrix dramatically reduces What happens in step 2 of endochondral ossification? (how does the periosteum form)

Answer 14

The chondrocytes apoptose and the cartilage calcifies now serving as a framework for the deposition of bone Due to the osteogenic potential of the perichondral cells, a thin layer of bone surrounds the diaphysis of the bone - known as the periosteum

Question 15

What is the periostuem bone collar continuous above and below at stage 2 of endochondral ossification?

Answer 15

Above and below the periosteal bone collar, it is continuous with the perichondrium

Question 16

There are a few steps occurring before stage 3 of endochondral ossification What is stage 3 of endochondral ossification?

Answer 16

This is where the primary ossification centre forms in the centre of the diaphysis with blood vessels and capillaries supplying the diaphysis and epiphysis

Question 17

What are the few steps happening between the cartilage calcifying, periosteal bone collar forming around the midpoint of the diaphysis and the primary ossification centre forming in the diaphysis?

Answer 17

Mesenchyme near the periosteum will differentiate into osteoprogenitor cells and blood vessels will invade the hyaline cartilage model Osteoprogenitor cells will differentiate into osteoblasts which will secrete osteoid that is quickly mineralised to bone. The oseoblasts surrounded in lacunae are now known as osteocytes

Question 18

What is the lacunae? What conects adjacent lacunae?

Answer 18

Lacunae is a small gap containing an osteocyte in bone or chondrocyte in cartilage Lacunae are connected by canaliculi

Question 19

Discuss stages 4 and 5 of endochondral ossification? Which ossification centres are important for longitudinal and diametric expansion until bone growth stops?

Answer 19

Secondary ossification centres form in the epiphyses - these are important for longitudinal and diametric expansion until growth stops Bone replaces cartilage, except at the epiphyseal growth plates and articular surfaces

Question 20

What is the final step of endochondral ossification?

Answer 20

The epiphyseal growth plate ossifies leaving epiphyseal lines and the cartilage at the articular surfaces remains

Question 21

We are now going to look at factors initiating ossification Primarily focused on is endochondral ossification as this is the type that takes place during vertebral column development What two transcription factors are vital in the ossification process?

Answer 21

Sox9 - SRY-box containing gene 9 and Runx2 - run-related transcription factor 2

Question 22

What is Sox9 essential in? What can happen if it is damaged or absent?

Answer 22

Sox9 (SRY-box containing gene 9) was found to be essential in the proliferation, differentiation and maturation of mesenchymal cells to chondrocytes Absence or damage of Sox9 can cause achondroplasia - a type of dwarfism characterized by short proximal limbs

Question 23

What cells express Runx2 in the chodnrogenesis/ossificaiton process? What can happen if it is absent?

Answer 23

Runx2 is expressed by prehypertrophic and hypertrophic chondrocytes and osteoblasts Consequences of Runx2 removal are fatal as they are needed to regulate development of a mineralized skeletion

Question 24

What is Sox9 essential in? What can happen if it is damaged or absent? What cells express Runx2 in the chodnrogenesis/ossificaiton process? What can happen if it is absent?

Answer 24

Sox9 is essential in proliferation, differentiation and maturation of mesechymal cells into chondrocytes Damage or absent Sox9 can cause achondroplasia Runx2 is expressed by prehypertrophic and hypertrophic chondrocytes as well as osteoblasts. Absence is fatal as you will not be able to mmineralize bone

Question 25

There is an important feedback loop regulating part of endochondral ossification What are the two proteins involved in this loop?

Answer 25

This would be Ihh (indian hedgehog) and PTHrP - parathyroid hormone related peptide

Question 26

How do Ihh and PTHrP serve as a feedback loop?

Answer 26

Ihh is secreted by pre-hypertrophic chondrocytes to allow PTHrP to control the differentiation of chondrocytes near the articular surface of the growth plate. This loops ensures there is a balance between the proliferation and maturation of chondrocytes

Question 27

What happens if Ihh is removed?

Answer 27

If Ihh is removed, PTHrp expression is reduced, preventing PTHrp from ensuring hypertorphic differentiation doesnt occur to early If Ihh is absent, osteoblast differentiation is also absent

Question 28

Wnts are glycoprotetins that were first discovered to be associated with ossification in 1994. They signal either via B-catenin-dependent pathways or without B-catenin What does Wnt stand for? What are the B-catenin dependent pathways known as? What are non B-catenin dependent pathways known as?

Answer 28

Wnt- stands for wingless-related integration site - to do with its discovery The B-catenin dependent pathways are known as the canonical Wnt pathways The signalling pathways without B-catenin are known as the non-canonical Wnt pathways

Question 29

What does Wnt/Beta catenin allow for? What happened in mouse models when B-catenin was removed?

Answer 29

The Wnt/Beta catenin signalling allows for osteoblasts to differentiatte When B-catenin was removed from mouse models, this process decreased and increased osteoclastogenesis

Question 30

When B-catenin was removed from the Wnt-Bcatenin signalling, osteoblast differentiation decreased and osteoclastogenesis increased What is osteoclastogenesis?

Answer 30

Osteoclastogenesis is the process by which osteoclasts are formed -these resorb bone

Question 31

When B-catenin was removed from mouse models, this process decreased. Osteoclastogenesis also increased which lead to decreased bone mass. Embryo death has also been reported due to abnormal endochondral ossification. The development of hypertrophic chondrocytes was slowed as well as blood vessel invasion. The removal of some Wnts can have serious consequences. What can the removal of Wnt 3 cause?

Answer 31

The removal of Wnt 3 can cause failure of both arms and legs to develop - tetra-amelia It can also cause more minor injuries like fewer permanent teeth

Question 32

Bone morphogenetic proteins (BMPs) are part of the Transforming Growth Factor-Beta protein family and their contributions to development are essential. When some BMPs are removed from mice, this can result in death or prominent defects. There are again many different types of BMPs When do BMPs become activated?

Answer 32

BMPs become activated when they bind to their specific membrane receptors

Question 33

BMP 2 is a primary factor involved in endochrondral ossiifcation What does it allow for and what can its absence cause?

Answer 33

BMP2 allows for the proliferation and maturation of chondrocytes and is important in fracture healing In the absence of bone morphogenic protein 2 - chondrodysplasia can develop - a group of diseases associated with artilage malformation

Question 34

In the absence of bone morphogenic protein 2 - chondrodysplasia can develop - a group of diseases associated with artilage malformation What can happen if there are mutations in BMP2 rather than complete removal?

Answer 34

Mutations in BMP 2 can cause a cleft palate

Question 35

What is the purpose of bone morphogenic protein 11?

Answer 35

BMP 11 is responsible for axial skeleton patterning from anterior to posterior, this is due to them changing the expression of the HOX genes

Question 36

Bone morphogenetic proteins (BMPs) are part of the Transforming Growth Factor-Beta protein family \* When some are removed, can result in death or prominent defects \* BMPs bind to specific membrane receptors \* What is the purpose of BMP 2 and 11 and what happens in the absence/mutation in BMP 2?

Answer 36

BMP 2 - allows for proliferation and maturation of chondrocytes \* Its absence leads to chondrodysplasia - a condition with cartilage malformations \* Mutations in BMP 2 can cause cleft palate \* BMP 11 - responsible for axial skeleton patterning from anterior to posterior due to changes in expression of HOX genes

Question 37

BMPs are also important in inducing the transcription factor expressed by prehypertrophic and hypertrophic chondrocytes as well as osteoblasts. What is this known as?

Answer 37

BMPs are important in inducing Runx2 expression Trancription factor expressed by pre-hypertrophic and hypertrophic condrocytes and osteoblasts - absence leads to death as there can be no bone mineralization

Question 38

And finally FGF/FGFR signalling - fibroblast growth factors and fibroblast growth factor receptors. There are many FGFs and FGFRs currently being studied. The most relevant factors are highlighted in this pic. What is FGFR 3 thought to control? Where in the growth plate is it? What can mutations cause?

Answer 38

FGFR3 is thought to control chondrocyte proliferation and is present in the proliferating zone of the growth plate Mutations in FGFR3 can cause achondroplasia

Question 39

Which fibroblast growth factor is the most likely activator of FGFR3? Where is this growth fractor expressed?

Answer 39

FGF18 is expressed in the perichodnrium and is thought to be the most likely activator of FGFR3

Question 40

As well as being expressed in the chondrocytes and osteoblasts, where else is FGF2 expressed? What does it have likely connections to?

Answer 40

FGF2 is expressed in the chondrocytes and osteoblasts as well as the limb buds It is thought to have connections to both the Ihh (involved in feedbakc loop to balance proliferation and maturation of chondrocytes) and BMP2 expression (also proliferation and maturation of chondrocytes as well as inducing Runx2) - both the Ihh and BMP2 pathways are affected when FGF2 is removed

Question 41

FGFR1/2 are again important in endochondral ossification, particularly in limb development. Where are FGFR1 and FGFR2 expressed?

Answer 41

FGFR1 is expressed in hypertrophic chondrocytes and is believed to control processes like differentiation and the production of the extracellular matrix FGFR2 is expressed later in the osteoblasts

Question 42

What can mutations in FGFR1 or FGFR 2 result in?

Answer 42

Mutations in FGFR 1 or 2 can result in Pfeiffer syndrome - this is where there abnormal early fusion of the skulll bones - prevents the skull from growing normally affecting the shape of the head and face

Question 43

Discuss \* FGFR3, \* FGF18, \* FGF2, \* FGFR1 and \* FGFR2

Answer 43

FGFR3 - thought to control chondrocyte proliferation, maturation & is present in proliferating zone of the growth plate - mutations can cause achondroplasia \* FGF18 - expressed in the perichondrium and thought to be the most likely activator of FGFR3 FGF2 - expressed in the chondrocytes & osteoblasts as well as limb buds - connections to both Ihh & BMP 2 expression \* FGFR1 and FGFR2 - important in endochondral ossification - FGFR1 expressed in hypertrophic chondrocytes and FGFR2 - expressed in osteoblasts - absence of either can cause Pfeiffer syndrome

Question 44

We have now discussed intramembranous ossification, chondrogenesis, endochondral ossification and factors initiating ossifciation (Sox9/Runx2, Ihh/PTHrP, Wnt/Beta-catenin pathway, BMPs, FGF/FGFR signalling) We will now discuss mechanobiology Define mechanobiology, mechanosensation and mechanotransduction? They will be discussed later on

Answer 44

Mechanobiology - a field, which focuses on how cell tissue mechanics and physical forces affect cell behaviour and tissue morphogenesis Mechanosensing - cell sensing mechanical signals created by the environment Mechanotransduction - translating the sensed mechanical signals into a response

Question 45

What does Wolff's law state?

Answer 45

To summarise - tissue (bone) will adapt to best fulfill its mechanical function Wolff's law states that the external shape and internal architecture of bone are determined by the external stresses acting on the bone - meaning a bone grows in responses to the stresses placed on it

Question 46

So, if the load on a bone progressively increased over time, then so too would the density and bone mass of that bone, to deal with the stresses \* What will happen if there is a reduction to the load placed on the bone? \* What are the cells encased within the bone matrix that cooordinate osteoblast and osteoclast formation? and in response to what?

Answer 46

A reduction of load on the bone will lead to a reduction of bone tissue The oscteocytes, encased within the bone matrix coordinate osteoblast and osteoclast formation in response to the mechanical stimuli (ie strain - how much the structure changes in shape in response to a load)

Question 47

What does Wolff's law fail to account for and therefore what theories were established?

Answer 47

Wolff's law fails to account for the hormonal influences governing the osteoclasts and osteoblasts in defining bone density To combine hormonal influences and mechanical forces such as stress, the Mechanostat theory and Utah Paradigm was formed

Question 48

The Mechanostat is a term describing the way in which mechanical loading influences bone structure by changing the mass (amount of bone) and architecture (its arrangement) to provide a structure that resists habitual loads with an economical amount of material. \* The bones response to a mechanical stimulus is threshold driven. \* Are the threshold points fixed and why? \* What are these threshold points known as?

Answer 48

The threshold points of how a bone responds to a mechanical stimulus is not fixed and can be altered by hormonal and metabolic factors These threshold points are known as minimum effective strains (MES') In the late 1980’s, Harold Frost created the concept of a control system in which a minimum effective strain (MES) is necessary for various stages of bone maintenance, using a thermostat as the basis of his idea - mechostat theory

Question 49

How does the parathyroid hormone effect minimum effective strains?

Answer 49

Parathyroid hormone makes osteoblasts more sensitive to mechanical stimuli, so these set points (MES), are altered to make a repsonse more likely Continuous PTH secretion can lead to bone resorption

Question 50

What is the difference between bone remodelling and modelling?

Answer 50

Remodelling and modelling are two antagonistic processes Bone remodelling - removes bone by resorption or maintains bone by resoprtion/formation Bone modelling - this is only adding bone

Question 51

What happens when the mechanical stimuls is low? (minimum effective strain for remodelling) What happens when the mechanical stimulus is high (minimum effective strain for modelling)?

Answer 51

When the mechanical stimulus is low, it reaches the MES strain for bone remodelling which resorbs unneeded bone and modelling is suppressed resulting in overall bone loss When the mechanical stimulus is high, it reaches the MES for bone modelling - bone remodelling is suppressed and bone modelling is activated resulting in overall bone gain

Question 52

What happens when the mechanical stimulus is too high?

Answer 52

When the mechanical stimulus is too high, there is internal damage to the bone matrix and the repair minimum effective strain is reached - the remodelling acts to repair damaged bone by creating woven bone on existing surfaces or new bone within the marrow cavity

Question 53

What are the three minimum effective strains for? Between remodeeling MES and modelling MES - there is an equilibrium where removal and addition of bone is balanced

Answer 53

\* Remodelling minimum effective strain - threshold point when the mechanical stimulus is low and remodelling resorbs unneeded bone \* Modelling minimum effective strain - threshold point when the mechanical stimulus is high and modelling results in overall bone gain \* Repair minimum effective strain - threshold point when mechanical stimulus is TOO high, resulting in remodelling forming woven bone one existing surfaces or new bone in the marrow cavity

Question 54

We have just discussed mechanobiolgy (Mechanobiology: A field, which focuses on how cell tissue mechanics and physical forces affect cell behaviour and tissue morphogenesis ) in relation to bone remodelling and modelling Lets now discuss its role in vertebral column development Quickly we will discuss intervertebral disc development What does it develop from? What types of collagen is the annulus fibrosus made from?

Answer 54

IV disc develops from Notochord - nucleus pulposus Sclerotome (derived from somites) - annulus fibrosus Annulus fibrosus is made up of circumfrential layers with the outer layers being Type I collagen and the inner layers being Type II collagen

Question 55

The annulus fibrosus able to resist forces that occur with axial rotation and give tensile strength. It is also able to resist the pressures that the nucleus pulposus creates. What forces is the nucleus pulposus exposed to?

Answer 55

The nucleus pulposus is exposed to more hydrostatic pressures

Question 56

Lets look at the mechanobiology and the IV disc \* Nucleus pulposus sensitive to mechanical forces throughout development \* Immature nucleus pulposus cells from different levels of vertebral column presented with distinct characteristics when viewed microscopically \* Unique stresses and compression levels on lumbar and caudal regions What are the lumbar vertebral bodies more exposed to and therefore what do immature nucleus pulposus cells look like?

Answer 56

The lumbar vertebral bodies are exposed to greater weight bearing forces and therefore the nucleus pulposus cells present with smaller vacuoles and more cell processes

Question 57

So looking at the intervertebral disc from a mechanobiologic stand point, it can be said that when stresses are applied, signals are altered and in turn, mechanical and biological factors unite to determine whether the tissue should undergo structural changes to accommodate. The effects of axial stresses and compression have also been studied on the annulus fibrosus. What did Hseih at al (2010) find to happen under these stresses?

Answer 57

Hseih et al (2010) found that under a large degree of stretching due to the axial and compressive forces on the annulus fibrosis, there has been a reduced proteoglycan synthesis by the annulus fibrosus cells (proteoglcyans are good at absorbing compressive forces due to their ability to absorb water)

Question 58

What part of the IV disc, did Hseih et al 2010 admit needed further studying as it is believed to be mechanobiologically active?

Answer 58

Hseih at el (2010) admitted the intralamellar compartment should be further studied as it is believed to be mechanobiologically active

Question 59

Iatridis et al. (2013) looked further into the effects of stress on the metabolism of intervertebral discs and stated that the response is dependent on what? WHat did they find that the mechanical loading induced?

Answer 59

Iatridis et al. (2013) stated that the response to stress on the metabolism of the IV disc is dependent on loading, magnitude, frequency and duration They found that mechanical loading induced specific mRNA and enzyme changes such as downregulation (decreased the quantity of these cellular components)

Question 60

Now lets looks at Effects of Muscle Paralysis and Neuromuscular Conditions on Skeletogenesis Ausk et al. (2017) discussed the effects of transient muscle paralysis by mode of Botulinum Toxin A (BTxA) injection \* What did Ausk et al. (2017) discover that botulimin toxin stimulates in the bones? \* Why was there a decrease in bone density after BTxA injection?

Answer 60

Botulimin toxin stimulates bone resoprtion within the medullary cavities of nearby bones, with associated inflammation There were a greater number of nuclei and osteoclasts numbers 72 hours after BTxA injection As remodelling was not in equilibrium, a decrease in bone density occured

Question 61

Aliprantis et al. (2012) also researched this concept and came to the conclusion that transient muscle paralysis leads to decrease in bone density due to what? What was the differentiation and activation of the osteoclasts caused by?

Answer 61

Transient muscle paralysis leads to decrease in bone density due to increase in osteoclastogenesis Differentiation and activation of the osteoclasts was activated by the upregulated expression of the RANKL protein (aka osteoclast differentiation factor)

Question 62

Foster et al. (2001) investigated the effect of Botulinum as a treatment for chronic lower back pain They concluded that paravertebral administration of BTxA in patients suffering from low back pain had positive effects and improved function Why was this deemed a controversial treatment?

Answer 62

The use of BTxA for chronic lower back pain was deemed a controversial treatment due to new studies showing the possible negative effects on bone mineral density due to increased osteoclastogenesis as a result of upregulated expression of the RANKL protein

Question 63

What is spinal muscular atrophy?

Answer 63

Spinal muscular atrophy is a group of inherited neurodegenerative comprising of muscular atrophy and weakness due to loss of spinal motor neurones, typically of the anterior horn

Question 64

Motor neurons control muscle movement. In cells, the SMN protein plays an important role in processing messenger RNA (mRNA), crucial for making proteins. What is the gene which spinal muscular atorphy is causes by which affected the SMN proteins? What is the severity of SMA dependent on?

Answer 64

Spinal muscular atrophy (SMA) is caused by a mutation in Survival motor neurone (SMN) gene 1 - SMN1 The severity of the disease is dependent on how many copies of SMN2 are present

Question 65

Where are SMN 1 and SMN2 located? What is the difference between the two?

Answer 65

SMN1 sits diretly beside SMN2 on chromosome 5 and is almost identical however due to a variation in a single nucleotide 840th nucleotide is C in SMN1 but T in SMN2, this mutation causes axon 7 to be spliced out in the latter. So most SMN proteins are degraded, some functional - only 10-20% of SM2 genes transcript a fully functional survival of motor protein .

Question 66

Patients with SMA have no copies have SMN 1 on chromosome 5 What does increasing copies of SMN 2 mean for the patient?

Answer 66

More copies of SMN2 = lower severity of spinal muscular atrophy (SMA (Fang et al., 2015) )

Question 67

Using the mechanostat theory and Wolff’s law, we can predict the outcome of osteogenesis in SMA. Bone mass will reduce due to muscle wasting and natural unloading. Fractures can also cause irreversible motor control loss. Congenital fractures can also occur, especially with SMA1, usually due to in -utero osteoporosis or osteopenia. How many copies of SMN 2 does each SMA type have?

Answer 67

* \* SMA type 1 - 1-3 copies of SMN 2 * \* SMA type 2 - 2-4 copies of SMN 2 * \* SMA type 3 - 3-4 copies of SMN 2 * \* SMA type 4 - 4-5 copies of SMN 2

Question 68

Amyotrophic Lateral Sclerosis (ALS) or Motor Neurone Disease Neuromuscular disease defined as death of motor neurones with subsequent progressive skeletal muscle atrophy (Zhu et al., 2015) What is duchenne muscular dystrophy?

Answer 68

This is a recessive condition characterised by muscle weakness and wasting due to mutation of the dystrophin gene -can lead to premature death

Question 69

What can the muscle weakness and wasting in DMD do to the bone?

Answer 69

The loss of muscle tension on the bone can cause poor bone quality, decrease of bone mineral density leading to osteopenia/osteoporosis

Question 70

What treatment for DMD is potentially thought to contribute towards the decrease in bone mineral density?

Answer 70

In a review by Morgenroth et al. (2012) it is discussed that loss of muscle tension and wasting which occurs in DMD is a cause of poor bone quality, decreased bone mineral density and osteopenia/osteoporosis However, it is not clear as to whether this is the only explanation, also believed that, due to its potent anti-inflammatory action, glucocorticoid (GC) therapy could compromise bone mineral quality and density.

Question 71

What is the autoimmune disorder caused by antibodies attacking the post-synaptic acetylcholine receptors at the neuromuscular junction?

Answer 71

This would be myasthenia gravis and due to the antibodies, this leads to muscle weakness and wasting

Question 72

What is the presenting age of myasthenia gravis? What problems can it cause on the bone?

Answer 72

The presenting age is under 40 women and over 60 in men MG presents with the same problems to the bone as DMD and due to glucocorticoids being used as immunosuppression, it can again be theorised that this is the cause of the low bone mineral density

Question 73

Now lets discuss the effects of mechanical stimulus on adult bones What is a mechanical stimulus? Again define mechanosensation and mechanobiology?

Answer 73

Mechanical stimulus - a mechanical stimulus is something like high pressure or stretching, causing the bones in our bodies to change and possibly adapt Mechanosensation - the cells sensing mechanical signals created by the environment Mechanotransduction - translating the sensed signals into a response

Question 74

Our weight-bearing skeleton must have capacity to appropriately respond to stimuli In an adult, what are 90-95% of bone cells? These cells are thought to be responsible for detecting the mechanical stimuli How many long processes can radiate from these cells? and what do these allow connection between?

Answer 74

In an adult 90-95% of bone cells are osteocytes. These contain up to 60 long process radiating from it to connect with another osteocyte forming the lacunar-canaliculi system This system allows the communication of osteocytes & surface cells Pic - osteocytes & radiating processes

Question 75

The osteocytes are the mechanosensors of the bone, lets talk about how they translate the sensed signals into a response (mechanotransduction) How osteocytes are able to sense mechanical stimuli and act accordingly is not yet completely understood. However there is a propular theory proposing how they do. Explain this thoery?

Answer 75

A popular theory is that osteocytes sense mechanical stimuli and act accordingly via mechanotransduction This allows physical forces (eg shear stress) to be transformed 2 bicohemical responses ( factors initiating ossificaiton as well as opening ion channels) & then for cells to respond biologically - osteoblasts and osteoclast activity

Question 76

A lot of research exists supporting the theory of shear stress by interstitial fluid flow. The best way to understand this is to think about a sponge retaining a lot of water. If you were to apply a force to the sponge by squeezing it, the water would flow out. What s thought to increase the flow of interstitial fluid in bone creating shear stresses?

Answer 76

It is thought that the pericellular matrix (the hand doing the squeezing) that envelops the osteocyte cells (the sponge), creates a pressure and inducing the flow of interstitial fluid

Question 77

Where does the interstitial fluid in the bone flow to?

Answer 77

The interstitial fluid in the bone flows to the volkmanns canals and haversion canals

Question 78

The flow of this intersittial fluid in the bone results in shear stresses which causes deforming of the osteocyte membranes What does the deforming of the osteocyte membranes cause for? What does the flow of the intersittial fluid allow for?

Answer 78

The deforming of the osteocyte membrane causes a biochemical reponse - the mechanotransduction theory (phsyical force eg shear forces, leads to biochemical responses, leads to biological responses) The flow of intersitial fluid allows for transport of essential nutrients and removal of any waste products