L12: The Physiology of Bone Flashcards
what are the 2 opposing processes occurring in bone and how can they cause disease
Bone-resorption- Imbalance this side leads to
Osteoporosis
Osteopenia, Rickets
Bone formation: Imbalance this side
Osteopetrosis
how do you classify bone structure
Classifications:
long bone
short bone
Macroscopic:
-Cortical Bone
-Cancellous (spongy)
Spicules, trabeculae
Microscopic
- Lamellar
- Wover
what is bone composed off
1-Osteoclasts
-Extracellular
Matrix
(osteoid)
2-Osteocytes
3-osteoblasts
what are the functions of the 3 principle cells
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
describe the difference between organic and inorganic bone material
Organic – cells and proteins
Inorganic – minerals, eg Ca2+ & PO4- (hydroxyapatite)
bone dominated by extracellular matrix – few cells
what is the Haversian system in lamellar bone
one type of microscopic organisation of bone tissue (the other is woven bone)
look at slide 8
describe how osteocytes arrive from osteoblasts
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
describe the function and features of Osteoclasts
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
what is the ruffle border
= 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
3 characteristics of bone
- Extracellular matrix is 70% minerals
- Plus abundant proteins and sparse cells
- High compressive strength and tensile strength
what are the acellular elements of bone
collagen fibres – protein, flexible but strong
hydroxyapatite – mineral, provides rigidity-calcium/phosphate crystals > 50 %
describe glycosaminoglycans
- long polysaccharides
- Highly negative
- Attract Water
- Repel each other
- Resists compression
Abundant in Cartilage
what are the growth factors effects on bone
They are revealed by osteoclast action
Which leads to proliferation & mineralisation
bone remodelling = bone turnover = the activation-resorption-formation sequence
How is bone remodelled
Osteoclasts resorb bone in Howships lacuna
Describe the bone remodel model
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
what occurs in the active resorption remineralisation sequence of bone
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
How can bone be formed
bone forms either as compact or cancellous and by either intramembranous or endochondral bone formation –
what is endochondral bone ossification
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.
what occurs in intramembranous ossification
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).
what are the factors governing remodelling
1-Recurrent mechanical stress
2- calcium homeostasis
-Plasma calcium is essential in maintaining structural integrity of skeleton
what are the effects of mechanical stress on the bone
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
what are the role of bisphosphonates in bone remodelling
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
describe the drugs used for osteoporosis treatment
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
Describe the process of osteopetrosis
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
what are the secondary effects of excess bone growth
Brittle (dense) bones
Blindness
Deafness
Severe anaemia
osteoclasts secrete acid
enables them to destroy bone. without the chloride channel this cant occur
describe phases 1 and 2 of fracture healing
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
what are the Phases of Fracture Healing: Stages 3 & 4
1) Hard callus formation:
- Lamellar bone replaces woven bone
2) Trabecular bone replaces (endochon.) lamellar bone
Original bone shape
Compact bone formed where appropriate
what are the Hormones of calcium regulation
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
how does PTH stimulate resorption via osteoblasts
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
describe how PTH release can cause different effects
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.
Describe Vitamin D production and activation
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+
what are the overall effects of vitamin d in the body
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+
how does vitamin D stimulate osteoclasts
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+
What are the causes of low plasma calcium
Loss:
- Pregnancy
- Lactation
- Kidney dysfunction
Low Intake:
- Insufficient ingestion of Calcium
- Rickets (low vit D)
Parathyroid dysfunction
what are the effects of chronic hypocalcaemia
Skeletal deformities
Increased tendency toward bone fractures
Impaired growth
Short stature (adults less than 5 feet tall)
Dental deformities
what are the effects of acute hypocalcaemia
Excitability
B – Bleeding A – Anaesthesia D – Dysphagia C – Convulsions A – Arrhythmias T – Tetany S – Spasms and stridor
BADCATS-mneumonic
what are the signs that we can test for acute hypocalcaemia
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
why does low plasma calcium lead to excitability
Hypocalcaemia makes membranes “more excitable” and “less stable”
Sodium is more able to leak through it
Explains latent tetany and its signs
does hypercalcaemia cause excitability
Hypercalcaemia paradoxically reduces excitability
By making membranes more stable
what are the signs and symptoms of hypercalcaemia
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
