L12: The Physiology of Bone

Question 1

what are the 2 opposing processes occurring in bone and how can they cause disease

Answer 1

Bone-resorption- Imbalance this side leads to
Osteoporosis
Osteopenia, Rickets

Bone formation: Imbalance this side
Osteopetrosis

Question 2

how do you classify bone structure

Answer 2

Classifications:
long bone
short bone

Macroscopic:
-Cortical Bone
-Cancellous (spongy)
Spicules, trabeculae

Microscopic

• Lamellar
• Wover

Question 3

what is bone composed off

Answer 3

1-Osteoclasts

-Extracellular
Matrix
(osteoid)

2-Osteocytes

3-osteoblasts

Question 4

what are the functions of the 3 principle cells

Answer 4

osteoblasts – on surface bone, produce protein component acellular matrix – regulate bone growth and degradation

osteocytes – quiescent mature cells embedded in bone matrix. They maintain bone.

osteoclasts – responsible for bone degradation and remodelling

Question 5

describe the difference between organic and inorganic bone material

Answer 5

Organic – cells and proteins
Inorganic – minerals, eg Ca2+ & PO4- (hydroxyapatite)

bone dominated by extracellular matrix – few cells

Question 6

what is the Haversian system in lamellar bone

Answer 6

one type of microscopic organisation of bone tissue (the other is woven bone)

look at slide 8

Question 7

describe how osteocytes arrive from osteoblasts

Answer 7

From mesenchyme:
-From precursor cells in bone marrow stroma

Osteoblasts are post-mitotic:

• Most osteoblasts will undergo apoptosis
• Number of osteoblasts  with age

A low % of osteoblasts will become osteocytes locked in lacuna

Question 8

describe the function and features of Osteoclasts

Answer 8

Function: Resorption
Multinucleate
40-100 micrometer in diameter.
(large )

Same precursor as monocytes (haematopoietic stem)

Phagocytose (bone matrix & crystals)

Secrete Acids

Secrete proteolytic enzymes from lysosomes

ruffled border = where bone resorption occurs

Question 9

what is the ruffle border

Answer 9

= a specialized part of osteoclast cell membrane that touches the surface of the bone tissue at a site of active bone resorption. It facilitates the removal of the bony matrix by increasing surface area interface for bone resorption. It is a sign that resorption is actively taking place

Question 10

3 characteristics of bone

Answer 10

• Extracellular matrix is 70% minerals
• Plus abundant proteins and sparse cells
• High compressive strength and tensile strength

Question 11

what are the acellular elements of bone

Answer 11

collagen fibres – protein, flexible but strong

hydroxyapatite – mineral, provides rigidity-calcium/phosphate crystals > 50 %

Question 12

describe glycosaminoglycans

Answer 12

• long polysaccharides
• Highly negative
• Attract Water
• Repel each other
• Resists compression

Abundant in Cartilage

Question 13

what are the growth factors effects on bone

Answer 13

They are revealed by osteoclast action

Which leads to proliferation & mineralisation

bone remodelling = bone turnover = the activation-resorption-formation sequence

Question 14

How is bone remodelled

Answer 14

Osteoclasts resorb bone in Howships lacuna

Question 15

Describe the bone remodel model

Answer 15

Osteoclasts (controlled by the signalling of osteoblasts), resorb bone in Howships lacuna

The osteoblasts deposit the bone onto pre-existing bone and does so forming osteons in different directions .

In adult life osteoblasts bring about bone deposition as part of remodelling and they secrete bone matrix directly onto pre-existing bone

Question 16

what occurs in the active resorption remineralisation sequence of bone

Answer 16

Surface osteoblasts control activation-resorption-mineralisation, because they detect the mechanical factors (stresses on that bone) and hormonal factors (from elsewhere in the body) that initially trigger bone remodelling.

They do this via IL-6 and other cytokines into the osteoclast which causes them to be activated (causing bone-resorption)

They signal back via liberated matrix bound growth factors

Question 17

How can bone be formed

Answer 17

bone forms either as compact or cancellous and by either intramembranous or endochondral bone formation –

Question 18

what is endochondral bone ossification

Answer 18

Endochondral ossification = bone formation based on a cartilage model. Chondrocytes proliferate and secrete extracellular matrix and proteoglycans. Osteoblasts (derived from osteoprogenitor cells) arrive and then osteoid is laid down and mineralisation begins. Precise modelling of the final bone is done by osteoclasts.

Question 19

what occurs in intramembranous ossification

Answer 19

Intramembranous ossification = bone formation without a cartilage model. Osteoblasts (derived from osteoprogenitor cells) lay down osteoid and begin mineralisation, forming tiny bony spicules. Nearby spicules join together into trabeculae (woven bone).

Question 20

what are the factors governing remodelling

Answer 20

1-Recurrent mechanical stress

2- calcium homeostasis
-Plasma calcium is essential in maintaining structural integrity of skeleton

Question 21

what are the effects of mechanical stress on the bone

Answer 21

1-inhibits bone resorption and promotes deposition (surface osteoblast and osteocyte network detect stresses)

2- without weight bearing bone rapidly weakens -(skeleton reflects forces acting on it )

3- eg, bed rest , lack of gravity

Question 22

what are the role of bisphosphonates in bone remodelling

Answer 22

For osteoporosis

E.g. Alendronate

inhibit osteoclast-mediated bone-resorption

the endogenous regulator of bone turnover
Accumulate on bone & ingested by osteoclasts
Interfere with osteoclasts metabolism

Question 23

describe the drugs used for osteoporosis treatment

Answer 23

Encourage osteoblast formation of bone:

• Teriparatide
• portion of human parathyroid hormone (PTH)
• Intermittent application activates osteoblasts more than osteoclasts

Prevent osteoclast maturation:

• Denosumab
• -Monoclonal Antibody that targets RANKL

Question 24

Describe the process of osteopetrosis

Answer 24

Molecular Mechanism
Osteoclasts cannot remodel bone

Defective Vacuolar proton pump or

Defective Chloride channel

Excess bone growth
Bone growths at foramina press on nerves

Brittle (dense) bones
Blindness
Deafness
Severe anaemia

Question 25

what are the secondary effects of excess bone growth

Answer 25

Brittle (dense) bones Blindness Deafness Severe anaemia

Question 26

osteoclasts secrete acid

Answer 26

enables them to destroy bone. without the chloride channel this cant occur

Question 27

describe phases 1 and 2 of fracture healing

Answer 27

1)Reactive Phase: Haematoma & Inflammation: -Blood cells enter wound -Haematoma forms -Inflammatory cells invade -Granulation tissue formed: Aggregation of Blood vessels & Fibroblasts Bone Precursor cells arrive from Periosteum ``` 2) Soft callus formation: Woven bone (or hyaline cartilage) join the pieces ``` Woven bone near BVs Fibrocartilage further away

Question 28

what are the Phases of Fracture Healing: Stages 3 & 4

Answer 28

1) Hard callus formation: - Lamellar bone replaces woven bone 2) Trabecular bone replaces (endochon.) lamellar bone Original bone shape Compact bone formed where appropriate

Question 29

what are the Hormones of calcium regulation

Answer 29

1) PTH – parathryoid hormone, parathormone - Parathyroid chief cells - Increases plasma Ca2+ 2) Vitamin D: 1,25-di-OH cholecalciferol (calcitriol) - Made in stages: Skin  Liver =Kidney - Increases plasma Ca2+ 3) Calcitonin - Made by thyroid C cells - “tones down” blood calcium - --Calcium goes into bone - --Used as a treatment for osteoporosis

Question 30

how does PTH stimulate resorption via osteoblasts

Answer 30

It does this via : - binding to PTH receptor on osteoblast , activating it, releases RANK Ligand - this binds onto the RANK of an osteoclast precursor cell, - causes it to differentiate into an activated osteoclast which can now perform bone resorption

Question 31

describe how PTH release can cause different effects

Answer 31

PTH applied continuously results in bone loss via increased osteoclast activity, but intermittent PTH results in increased osteoblast number and osteoblast mineralisation activity in osteoporosis; the net effect of intermittent PTH is bone strengthening.

Question 32

Describe Vitamin D production and activation

Answer 32

SKin- Choleciferol (D3) is hydroxylised in the liver forming 25-oh-cholecalciferol. This once it goes through the kidneys are transformed into 1,25-di-OH cholecalciferol (calcitrioil) - this leads to increased levels of calbindin in the gut enterocytes - this increases intestinal absorption of ca2+ and in the kidneys too this leads to an overall increase in plasma ca2+

Question 33

what are the overall effects of vitamin d in the body

Answer 33

Increases intestinal Ca2+ absorption Increases calbindin Stimulates kidneys to reabsorb calcium stimulates osteoclasts indirectly via osteoblasts This is a comparatively weak effect Vitamin D facilitates bone remodelling and thus increases serum Ca2+

Question 34

how does vitamin D stimulate osteoclasts

Answer 34

stimulates osteoclasts indirectly via osteoblasts. osteoblast is principle target of vitamin D stimulates osteoblasts to produce cytokines that accelerate maturation of osteoclasts thus facilitating bone remodelling Thus, vitamin D remodels bone and increases serum Ca2+

Question 35

What are the causes of low plasma calcium

Answer 35

Loss: - Pregnancy - Lactation - Kidney dysfunction Low Intake: - Insufficient ingestion of Calcium - Rickets (low vit D) Parathyroid dysfunction

Question 36

what are the effects of chronic hypocalcaemia

Answer 36

Skeletal deformities Increased tendency toward bone fractures Impaired growth Short stature (adults less than 5 feet tall) Dental deformities

Question 37

what are the effects of acute hypocalcaemia

Answer 37

Excitability ``` B – Bleeding A – Anaesthesia D – Dysphagia C – Convulsions A – Arrhythmias T – Tetany S – Spasms and stridor ``` BADCATS-mneumonic

Question 38

what are the signs that we can test for acute hypocalcaemia

Answer 38

Chvostek’s sign = Tapping masseter leads to twitch on same side of face Trousseau's sign /Carpopedal spasm = Trousseau’s sign = Hand spasm after 3 minutes with blood pressure cuff in place (above systolic pressure) DI-George syndrome: rare (1:4000) genetic anomaly caused by the absence of the long arm of one of the two 22nd chromosomes. The resulting developmental anomaly presents in many different ways, but typically there are issues with the mediastinum that lead to an absent thymus (poor T cell function) and underdeveloped parathyroid glands

Question 39

why does low plasma calcium lead to excitability

Answer 39

Hypocalcaemia makes membranes “more excitable” and “less stable” Sodium is more able to leak through it Explains latent tetany and its signs

Question 40

does hypercalcaemia cause excitability

Answer 40

Hypercalcaemia paradoxically reduces excitability | By making membranes more stable

Question 41

what are the signs and symptoms of hypercalcaemia

Answer 41

Can be asymptomatic Reduced excitability Esp. --Constipation -Depression + other psychiatric Abnormal heart rhythms: - Short QT interval, - ST segment gone - Widened T wave Severe hypercalcemia - Coma - Cardiac arrest