Case 2: Physiology (Bone Tissue) - Coggle Diagram
Case 2: Physiology (Bone Tissue)
Bone Tissue has special functions.
Outline the functions of the Bone Tissue
Bone provides a mechanical framework on which muscles can act to provide movement.
Bone provides a protective casing. Eg: Ribcage around thoracic organs. Skull for the brain
Haematological/ Immunological : Bone contains bone marrow from which bone blood cells and immunological cells are synthesised.
Pharmacological: Bone is a site of drug and fluid infusions
Physiological: Bone is part of fluids and electrolytes.
Outline the structural components of the Bone Tissue
Bone is made up of:
70% Salt deposits
30% of organic matrix
The salt deposits are then further made up og:
And other trace elements (Na+ and K+)
What are the functions of Calcium ?
Calcium has Structural, Cofactor and Signaling Functions.
Provides structural integrity of bone and teeth
Cofactor Functions include
Calcium acts as a cofactor reactions such as the Clotting / Complement cascading process
Calcium also acts as a cofactor in protein synthesis and apoptosis
Calcium acts as a second messenger and can induce gene expression
Calcium is able to induce excitation-contraction and secretion
Calcium can also modulate nerve/ membrane excitability (formation of action potentials)
Hypercalcemia's membrane excitability is low as Calcium repels the Sodium Ions, vice versa
Outline the Calcium distribution in the body
99% of Calcium is placed in the bone
1% is in the cells
Where o.1% is in the plasma
We can ONLY measure the calcium in the plasma
Outline the distribution of Calcium in the Plasma
50% of Calcium in the plasms is bound to proteins. eg: Albumin
9% of the Calcium in the plasma is bound to Anions. Eg: Bicarbonate or citrate
41% of Calcium in the plasma is known as the free portion.
If an individual as low albumin levels in the plasma
There is less albumin to bind proteins
Therefore, more proteins in the free portions
Ionized/ Free portion of calcium executes physiological reactions - Calcium is bioactive portion
Portion is tightly regulated by Parathyroid Hormone (PTH)
Describe the sections of the body which can affect the Plasma Calcium
Calcium can come from diet through the Splanchnic Blood Flow from the intestine.
It can then be lost through fecal loss.
Cellular components can also provide or take away calcium from the Plasma
Plasma calcium can also communicate with the renal components
This is because kidneys have the ability to store calcium and loss it through urine loss
Secondary regulatory site of plasma calcium
Calcium is taken from the plasma to make bone tissue
Bone tissue are dissolved and calcium is retuned back to plasms
How is Calcium Handled in the GIT ?
Bowel Input: Calcium in the intestinal system comes from diet, bowel juices or tissue breakdown
Absorption: The calcium is then absorbed into the duodenum
Within the duodenum there are specialised epithelial cells, that can allow calcium to pass from one end to another.
Calcium does this in 2 ways:
Depends on the concentration of calcium on the lumen side.
Allows ONLY a small portion to be absorbed
Active transport mechanism is Vitamin D dependent
Vitamin D activation is enhanced by the PTH (Parathyroid Hormone)
PTH stimulated the synthesis of a Calcium (Ca2+) binding protein known as Calbindin
Calbindin will bind calcium so that calcium ends up accumulating in the epithelial cell.
When Calcium builds up, it forms a gradient between the amount of calcium in the cell compared to the amount of calcium outside the cell.
Therefore, by Facilitated Protein through a transport protein it can take advantage of this gradient to move calcium out of the cell.
Bowel Output: Calcium can be lost through fecal loss.
Renal Ca2+ Handling
The nephron is the smallest functional unit of the kidney
List the components of the nephron
Loop oh Henle
How is Calcium handled in the Kidney ?
Ionized (Free) calcium is filtered in the glomerulus.
Afterwards it ends up the tubular system
Bulk of (65%) calcium in the tubular system is reabsorbed in the proximal tubule.
Through Paracellular Transport or through Ca Channels.
Loop of Henle
25% of Calcium is reabsorbed in the Loop of Henle
10% is reabsorbed in the Distal Tubule
Through Epithelial Calcium Channels (ECaC)
Protein involved is Transient Receptor Potential V5 (TRPV5)
Reabsorption is enhanced by Vitamin and PTH to prevent Ca excretion
Vitamin D is also activated by the kidneys
If things are not reabsorbed then they are lost with urine.
Cellular Ca2+ Handling
How is Calcium Handled in the Cells ?
In the cell there is Calcium in the: Plasma, Cytoplasm and Endo- or Sarcoplasmic Reticulum
However, there is a different concentration of Calcium in each compartment.
The Plasma has the highest concentration of Calcium
Cytoplasm has the lowest concentration of Calcium
Reticulum has the second highest concentration of Calcium
Therefore, calcium is readily able to move from the plasma to the cytoplasm or from the reticulum to the cytoplasm
These movements are concentration gradient driven
When Calcium Channels are open, Calcium will move from the plasma to the cytoplasm.
This is driven by the chemical-electrical gradient
Calcium can exit the cytoplasm and enter into the plasma via the Calcium Pump (Na-Ca Exchanger)
Sodium will then exit the plasma and enter into the cytoplasm via the Calcium Pump
Calcium can also be released from the sarcoplasmic reticulum via the receptors such as Ryanodine or IP3 receptors
The movement of calcium is from the sarcoplasmic reticulum to the cytoplasm due to the existing calcium concentration gradient
Calcium then moves actively from the cytoplasm into the sarcoplasmic reticulum vis the SERCA Pump
NOTE: Movement will move calcium for excitement.
Bone Components: Phosphate
Phosphate is predominantly an intracellular ion
Describe the distribution of Phosphate in the body
85% of phosphate is in bone
15% of phosphate is in the cells
Less than 1% is in the plasma
List the functions of Phosphate
Phosphate has Metabolic, Homeostasis and Structural Functions
Phosphate is responsible for a variety of metabolic reactions:
Oxygen Transport through 2.3 DPG
Energy storage via the ATP molecule
Acid-base balance: Phosphate can bind Hydrogen which is an acid.
Phosphate acts as a buffer system
Phosphate is used to make bone. (using Bisphosphonates)
Phosphate is used to make the membrane structure: Phospholipid Bilayer
How is Phosphate Metabolized in the Plasma and GIT ?
The plasma has 0.8 - 1.4 mmol/L
Phosphate is not as tightly regulated in the plasma as Calcium (Ca2+)
Phosphate is able to bind to Hydrogen to form phosphate buffer
Phosphate in the plasma acts as a storage site for Hydrogen ions.
Almost all dietary Phosphate is absorbed
Vitamin D promotes the trans-epithelial fluxes
Renal Phosphate Handling
How is the Phosphate handled in the Kidney ?
Phosphate is filtered in the glomerulus
80% of Phosphate is reabsorbed in the proximal tubule
This occurs through co-transporters: co-transport transport phosphate back into blood from the proximal tubule.
10% is reabsorbed in the distal tubule
Phosphate is regulated in the Distal Tubule.
Parathyroid Hormone will increase the loss of Phosphate
Vitamin D will stimulate the conservation of Phosphate
When we measure in blood that a person has a high PTH, their Blood Phosphate level is low. As the phosphate has been lost in the kidney.
Therefore, a high Ca2+ and a low Phosphate level will indicate that there is a high PTH level and activity.
Phosphate Buffer system acts in the Collecting Tubule.
How is Magnesium distributed in the body ?
53% of Magnesium is in the Bone
27% is in the muscle
19% is in the soft tissue
0.3% is in the Plasma
How is Magnesium distributed in the Plasma ?
33% of Mg2+ in the plasma is Protein-Bound
5% of Mg2+ in the plasma is anions
62% of Mg2+ in the plasma is ionized (free)
Outline the functions of Magnesium
Magnesium has Metabolic, Structural and Other Functions.
Magnesium acts as an enzyme cofactor, and because of its ability to bind to ATP, it is a cofactor which makes ATP useful for cells.
Magnesium is an energy substrate as it can bind to ATP to form MgATP
-Magnesium is also used in the making of bone structure
Magnesium is used to make structures of Ribosomes, nucleic acids and proteins
Magnesium interact with Calcium: Magnesium has a greater charge than Ca2+. Therefore it can repel Calcium.
If someone has Hypermagnesemia, the individual will have muscle paralysis as the Magnesium will repel calcium by electrostatic repulsion from calcium channels.
Calcium channels will therefore not be able to enter a muscle to trigger an excitation. Person will become Hypotonic with Hypermagnesemia
Magnesium regulates protein functions.
GIT Mg2+ Handling
Explain how Magnesium handled in the GIT ?
Magnesium is absorbed in the GIT at the Jejunum and Ileum
Absorption is promoted by the Vitamin D.
The entry of Magnesium from the lumen and into the Blood occurs via 2 transport system:
Paracellular transport is when Magnesium can pass through cells to reach the blood.
This transport system is dependent on the concentration gradient
As long as there is greater Magnesium concentration the lumen of the gut compared to the blood.
The Magnesium will find it way between the cells to the blood.
Transcellular transport is when Magnesium has to find its way through the epithelial cells
Magnesium will enter the Apical Side of the epithelial cell via the TRPM6 (Transient Receptor Potential Melastatin Type 6) Channels
Channels will allow Magnesium into the epithelial cell via the Electrochemical Gradient as the inside of the cell is negatively charged
This transport system is dependent on the
Once inside the epithelial cell, the Magnesium is then transported via transport proteins to the blood through the process of Facilitated Diffusion.
Facilitated Diffusion takes advantage of an existing electrochemical gradient to move objects down the concentration gradient
Magnesium Renal Handling
Explain how Magnesium is reabsorbed in the Kidney
15% of Magnesium is reabsorbed in the Proximal Tubule via Paracellular Transport
70% of Magnesium is reabsorbed in the Ascending Loop via Paracellular Transport with the help of Paracellin Proteins.
Magnesium is then reabsorbed in the Distal Convoluted Tubule via Transcellular Transport through the:
Epithelial Apical Channels
Patients with mutations in TRPM6 will have Familial Hypomagnesemia as they cannot reabsorb Magnesium in the Distal Tubules
Therefore, Magnesium is lost in the kidney
Will require a continuous supplement of Magnesium
10% of Magnesium is lost in the Collecting Duct
Bone Tissue: Structural Components
Outline the Structural Components of the Bone Tissue
Bone Tissue is made up of:
The organic matrix is then made up of the following:
Collagen Fibres (90%)
Collagen fibres are arranged in an overlapping pattern
This arrangement of collagen fibres allows the Matrix to provide Tensile Strength/ Resistance
Tensile resistance prevents tearing
The Matrix also has Ground Substance between the Collagen fibres.
Ground substance contains Extra-Cellular Fluid (ECF) and Proteoglycans
Salt deposits is made up of:
Salt deposits provide Compressional strength when the bone is placed under compression
Precipitation inhibitors such as Pyrophosphate that inhibit the formation of bone in unwanted places as well as anytime.
Therefore, if there is precipitation of bone in unwanted places, that bone is known as Ectopic Calcification
If this happens in the Blood Vessels the blood vessels harden this is known as Arterial Sclerosis
Describe the structure of a typical long bone
A long bone has an Epiphysis on either end of the bone.
A diaphysis (Shaft) between the 2 Epiphysis.
The Epiphyses contain articular cartilages to form joints with the other bones.
The bone has and Epiphyseal Plate that allows for bone growth and lengthening of the bone.
Diaphysis contains a Periosteum which can be modified to allow bone growth and widening of the bone.
Describe the cross-sectional structures seen in the bone
Outer Periosteum known as the Compact Bone.
Inner Part is known as Spongy Bone and is close to the bone marrow.
Osteocytes that form a pattern in the bone
Lamella which is made up of concentric layers of compact tissue that surround the Haversian canals
Blood vessels moves within Haversian Canals
The combination of pattern where Blood vessels are surrounded by Lamella is known as the Osteons/ Haversian system
NOTE: Bone is a living structure along with Osteocytes.
Describe the structure of an Osteon
Osteon has a blood vessel at the center of the Haversian Canal
Osteoblast follow after the blood vessel
Osteoblast are a stem cell derived cells
Osteoblasts are responsible for building bone tissue
Osteoblasts then connect to Osteocytes
Osteocytes are quiescent cells which form the particular pattern of the bone
Connections of the Osteocytes allow for spaces to form around these cells.
Spaces are known as Canaliculi, which contain communicating substances
Between the Osteoblasts and the Osteocytes there are Gap Junctions which allow for intercellular communication
Osteocytes "builders" are trapped within their concrete. They can be recruited through communication systems and can become Osteoblasts
Osteoclasts ae connected to Osteocytes
Osteoclasts are a form of Macrophages
As a result: Osteoclasts dissolve or destroy bone tissue to prepare for bone remodeling
Bone Formation: Deposition and Calcification
How do Osteoblasts build bone tissue ?
Osteoblasts are responsible for building bone tissue.
Osteoblasts secret collagen, ground substance, alkaline and phosphatase.
These structures and fibres will then polymerize to form soft tissue also known as Osteoid Tissue
Sometimes, osteoblasts become trapped in the osteoid tissue and become Osteocytes (form of bone), (quiescent forms of osteoblasts)
How does this Osteoid Tissue harden ?
With the deposition of Hydroxyapatite crystals from the Calcium/ Phosphate precipitation the osteoid bone is able to harden
This process of hardening is regulated by precipitation Inhibitors called Pyrophosphate that prevent Ectopic Calcification.
When precipitation (hardening of bone) occurs after a few days bone will form Amorphous Bone which is fairly soft.
After a few weeks the bone will form Crystalline Hydroxyapatite (Bone)
How do Osteoclasts breakdown bone tissue ?
Osteoclasts are regulated by the Parathyroid Hormone (PTH)
PTH aims to breakdown bone to release more Calcium into the plasma
Because osteoclasts come from a lineage of macrophages they produce villus-like extensions that can phagocytose bone tissue
Proteolytic enzymes that digest bone matrix
Acids such as lactic acid, citric acid dissolve the salts in the bone tissue
Osteoclasts will phagocytose other debris.
Regulation: Cellular Signals
Outline how do cellular signals regulate bone changes ?
Osteoblasts are regulated by the PTH
Osteoblasts can produce molecules that can bind to macrophages or pro-osteoclasts to stimulate them to become osteoclasts.
This is done through the production of molecules that can bind to receptors on the macrophages.
These receptors are known as RANK (Receptor Activator of Necrosis Factor)
Osteoblasts produce the RANK ligand
When the RANK Ligand binds to RANK receptor, the macrophages proliferate and become typical Osteoclasts.
This promotes bone destruction.
In turn the Osteoclasts have receptors known as Osteoprotegerin
Osteoblasts will then produce an Osteoprotegerin Ligand that binds to the Osteoprotegerin of the Osteoclasts.
the binding of the Osteoprotegerin Ligand to the Osteoprotegerin receptor will inhibit the Osteoclast activity.
This promotes bone formation.
How is Osteoclast activity regulated
RANK binding stimulates osteoclast activity
Osteoprotegerin binding inhibits osteoclast activity
How do we measure osteoclast activity ?
To monitor osteoclast activity we:
Measure the RANK Ligand and compare it to the amount of Osteoprotegerin Ligand
This can tell us whether a bone is being formed or a the bone is undergoing destruction, by measuring bone density
Regulation: Integrated communication
Osteoblasts can communicate with macrophages (pro-osteoclasts) and stimulate them to proliferate into osteoclasts.
Increase osteoclast activity: bone destruction
Osteoblasts can directly communicate with osteoclasts and inhibit their activity: bone formation
Osteoblasts communicate with osteocytes, activate the osteocytes to become osteoblasts: bone building
List the factors that communicate bone cells
Outline the process of Bone Growth
Bone can undergo growth through widening and lengthening
Osteoclasts work on the periosteum of the bone
With subsequent deposition of bone by the osteoblast
This widens the bone
Lengthening of the bone occurs via the epiphyseal plate
Due to the presence of chondrocytes undergoing division. The epiphyseal plate will grow.
So that the epiphyseal plate and the bone increases in size vertically
When the bone has reached its full length, the bone will undergo modification where the Calcification by osteoclasts and Resorption and Deposition by osteoblasts will shape the epiphyseal plate to go back to its original plate.
Without changing the new bone length
Define Bone remodeling
Bone remodeling is the ongoing formation and absorption of bone.
What happens during bone remodeling ?
Osteoclasts create tunnels around the blood vessels through bone destruction
Osteoblasts then invade and create new bone
Outline the advantages of bone remodeling and why it needs to occur ?
Allows the bone to adjust to stress
Allows for the correction in the shape of the bone example, after a fracture
Allows for the replacement of brittle, old bone
Outline fracture repair
When there is a bone fracture resulting in the Hematoma and Clot Formation, this activates Osteoblasts
As well as the recruitment of other osteoblasts from stem cells
This allows for the formation of the Callus between bone fragments through callus deposition
Eventually, remodeling and callus removal will occur
Regulation of Bone Physiology: Vitamin D
Describe the formation of Vitamin D
Outline the regulation of Vitamin D
The production of the 25-Hydroxy Calcitriol or 25-Hydoxy Vitamin D3 in the Liver provides a negative signal to Cholecalciferol in the skin
This helps to conserve unconverted Vitamin D3 in the skin
Outline the function/ actions of Vitamin D
Increases the absorption of Ca2+ in the GIT via the epithelial Ca2+ binding protein
Increases the phosphate absorption in the GIT
Decreases renal excretion of Calcium and Phosphate
What produces PTH ?
PTH is synthesised by the Chief Cells in the Parathyroid
Why is the PTH important
PTH is essential for life as it regulates calcium
PTH is stimulated by a decreases in the serum Calcium
Outline the actions of the PTH
Increases the concentration of calcium in the plasma by increasing bone absorption or bone destruction
And then decreases renal excretion of calcium
PTH decreases the concentration of phosphate, although it promotes bone absorption through the destruction of the bone
PTH stimulates the increased loss of Phosphate in renal excretion
Describe how Calcitonin is produced
Calcitonin is produced in the Parafollicular cells of the Thyroid Gland
What are the actions of Calcitonin ?
Stimulates opposite effects to the PTH, but these effects are mild
Rapid effects is that it decreases osteoclastic reabsorption
Long term effects is that it suppresses the formation of osteoclasts
What is the purpose of oestrogen ?
Oestrogen prevents the loss of bone.
Outline the actions of oestrogen in inhibiting bone loss
Inhibits osteoclasts, therefore decreasing bone resorption
Bone building activity of osteoblasts is regulated via the oestrogen receptor
That is way during menopause, when there is a decrease in oestrogen levels in the body. The bone density changes.
Other cytokines and growth factors
IL-6, IGF-1, Transformational GF (TGF beta)
What are the actions of Glucocorticoids ?
Induce bone loss
inhibit GIT absorption of calcium
Induces secondary Hyperthyroidism
Direct effects via Cytokines and PG