1. CELLULAR STRUCTURE OF BONE Flashcards
1
Q
What are the four functions of bone?
A
- STRUCTURAL - provides shape & structure
- MECHANICAL - allows for movement by providing attachment sites
- PROTECTIVE - protects internal organs such as the heart & brain
- METABOLIC - reserve for calcium & other minerals
2
Q
What two components make up bone?
A
- INORGANIC COMPONENT (65%) - Calcium hydroxyapatite containing calcium, phosphorus, sodium, magnesium
- ORGANIC COMPONENT (35%) - Consists of bone cells, extracellular protein matrix mainly collagen
3
Q
What are the three types of classification for bones?
A
- Bones can be classified according to anatomy or structure
1. ANATOMICAL CLASSIFICATION
2. MACROSCOPIC STRUCTURE
3. MICROSCOPIC STRUCTURE
4
Q
What are the 5 types of anatomical bone?
A
- FLAT - skull, scapula, sternum (protective)
- LONG - bones of the limb e.g humerus, ulna, radius, tibia
- SHORT/CUBOID - carpals & tarsal bones
- IRREGULAR - vertebrae & some of the skull bones
- SESAMOID - embedded in muscle e.g patella
5
Q
*What are the two tissue types for the macroscopic structure of bone?
A
- TRABECULAR/CANCELLOUS/SPONGY - made up of trabeculae (bony plates) with high metabolic activity & provides strength
- CORTICAL/COMPACT - thick base making up the shaft
6
Q
How is bone classified according to microscopic structure?
A
- WOVEN BONE (IMMATURE)
2. LAMELLAR BONE (MATURE)
7
Q
*What are the properties of cortical bone?
A
- Cortical/compact bone is mainly for structural, mechanical & protective functions
- It is highly calcified (80 -90%)
- Long bones, make up 80% of the skeleton
- Appendicular skeleton
8
Q
- What are the properties of trabecular bone?
A
- Trabecular/cancellous/spongy bone is mainly involved in metabolic functions
- Large surface area
- Vertebrae & pelvis - make up 20% of the skeleton
- Axial skeleton
- Not very mineralised (15-25%)
9
Q
Describe the structure of a long bone?
A
- EPIPHYSIS - found at the ends of the bone, distal & proximal
- DIAPHYSIS - found in the middle of the bone, also known as the shaft
- METAPHYSIS - found beneath the growth plates & separate the epiphysis & the diaphysis
10
Q
*What are the two types of bone development?
A
- INTRAMEMBRANOUS OSSIFICATION - involved in FLAT BONE formation
- ENDOCHONDRAL OSSIFICATION- involved in LONG BONE formation
11
Q
What is intramembranous ossification & endochondral ossification?
A
-INTRAMEMBRANOUS: Involved in the formation of flat bones
- Osteoblasts differentiate directly from mesenchymal precursors in the connective tissue
ENDOCHONDRAL:
- Forms long bones
- Bones develop from pre-existing cartilage model
12
Q
Describe the formation of the primary ossification centre in endochondral ossification?
A
- In foetal develop, a hyaline cartilage scaffold will from within limb buds
- After birth, the cartilage will expand but most of the bones in a newborn will be cartilage
- As the cartilage continues to expand, it will become hypoxic as it lacks vasculature
- Blood vessels invade the cartilage scaffold bringing in blood & precursors
- The precursors differentiate and convert the diaphysis into bone which is known as the PRIMARY OSSIFICATION CENTRE
13
Q
Describe the formation of the secondary ossification centre during endochondral ossification
A
- Ossification expands from the primary ossification centre towards the epiphysis
- A SECONDARY OSSIFICATION CENTRE forms, which is separated from the primary ossification centre by the growth plates
- Development continues as cartilage is converted into bone at the primary & secondary ossification centres
14
Q
What marks the end of bone development by endochondral ossification?
A
- Ossification of the growth plates & fusion of the secondary & primary ossification centres marks the end of bone development
15
Q
What are three zones of organisation for the chondrocytes in the growth plate?
A
- Chondrocytes are mature cartilage cells, they can be organised into three distinct zones passing through them throughout their lifespan
1. RESERVE ZONE
2. PROLIFERATIVE ZONE
3. HYPERTROPHIC ZONE
4. OSSIFICATION ZONE (once cartilage has been converted to bone)
16
Q
**Describe the development of the chondrocytes in the growth plate leading to the three zones
A
- RESERVE ZONE -The reserve zone contains stem cell populations for the growth plate which proliferate slowly. The chondrocytes are located near the epiphysis near the blood supply in the secondary ossification centre
- PROLIFERATIVE ZONE - Cells in this region are highly proliferative & form distinct column like structures. As the chondrocytes move further away from the blood supply, they undergo HYPERTROPHIC DIFFERENTIATION
- HYPERTROPHIC ZONE - The further away from the blood supply the larger the cells are. Eventually the chondrocytes will undergo apoptosis due to the lack of vasculature, leaving behind an extracellular cartilage matrix
- OSSIFICATION ZONE - The extracellular cartilage mineral matrix will be ossified to form bone by the bone cells
17
Q
What are the three types of specialised bone cells?
A
- OSTEOCYTES - mature bone cells
- OSTEOCLASTS - multi-nucleated cells that resorb bone
- OSTEOBLASTS - Immature bone cells that form bones cells
18
Q
What are osteocytes & their structure?
A
OSTEOCYTES are mature bone cells
- Osteocytes form a mechanosensory network
- Osteocytes are connected via dendritic processes through canalicular channels
- Osteocytes are embedded in the lacunae of trabeculae
19
Q
What are osteoclasts?
A
- Osteoclasts are giant multi-nuclear cells that form from the fusion of macrophages
- Osteoclasts are involved in resorbing/breaking bone
20
Q
How do osteoclasts resorb bone?
A
- Osteoclasts bind to & seal off a portion of bone beneath them
- They secrete acids to break down the inorganic component & enzymes to break down the organic component
21
Q
What are osteoblasts?
A
- Osteoblasts are immature bone cells that from new bone by secreting osteoid
22
Q
How do osteoblasts form new bone?
A
- Osteoblasts secrete osteoid
- The osteoid contains the organic component of bone which can then be mineralised over time to form bone
- Or, the osteoblasts can become embedded in the osteoid & differentiate directly in osteocytes
23
Q
What’s the bone remodelling cycle & it’s importance?
A
- The bone remodelling cycle is a balance between bone formation & bone resorption
- Any imbalances can lead to disorders
- Small portions of our bone are resorbed & reformed everyday, in 7 years our whole skeleton will have been replaced
24
Q
Describe the 4 stages of the bone remodeling cycle?
A
- MICROFARCTURES -Microfractures can occur due to stresses & tend to occur in older bone
- RESORPTION - Microfractures are detected by osteocyte mechanosensory network, causing osteoclast differentiation. Osteoclasts resorb damaged bone
- FORMATION - Once the osteoclasts have finished resorbing bone, they undergo fission to form mon-nuclear individual cells. The osteoblasts then secrete osteoid to from new bone repairing the damaged bone
- REPAIRED BONE - The bone becomes mineralised & has been repaired
25
How can an imbalance in the bone remodeling cycle cause bone loss?
- The balance between bone formation & resorption is disrupted & favours boe resorption. This leads to a net loss of bone mass
- Could be due to:
1. Excess resorption
2. Insufficient bone formation
26
How can an imbalance in the bone remodelling cycle cause bone gain?
- The balance between bone formation & resorption favours bone formation. There's a net increase in bone mass
- Could be due to:
1. Excess bone formation
2. Insufficient bone resorption
27
What are the two types of control of bone remodeling?
1. ENDOCRINE CONTROL (distant) - PTH, Thyroid hormone, oestrogen
2. PARACRINE CONTROL (local) - RANKL, Wnt Signaling
28
What two factors are involved in Osteoclast differentiation?
- Osteoclast differentiation occurs via RANKL signaling (Receptor activator of NF Kappa beta ligand)
1. RANKL = stimulates osteoclast differentiation
2. OPG = inhibits osteoclast differentiation
- The ratio of RANKL to OPG determines the levels of osteoclast differentiation
29
How does RANKL affect osteoclast differentiation?
- RANKL binds to to the RANK receptor to trigger a signalling cascade which leads to osteoclast differentiation, maturation & survival
- RANKL is produced by osteocytes & osteoblasts
30
How does OPG affect osteoclast differentiation?
- OPG is an antagonist for the RANK receptor & inhibits osteoclast differentiation
- In the bone remodeling cycle, once a sufficient depth of bone has been resorbed the ratio of OPG:RANKL changes to increase OPG to decrease the rate of osteoclast differentiation
31
What signaling pathway is involved in Osteoblast differentiation & describe the steps?
- Wnt signalling is responsible for osteoblast differentiation
1. A Wnt ligand binds to the Frizzled receptor (Fz)
2. The Fz receptor must be in complex with LRP 5/6 (low-density lipoprotein related protein) in order to be active
3. Binding of Wnt ligand to the active Fz causes osteoblast differentiation
32
What two antagonists inhibit osteoblast differentiation & how?
1. SCLEROSTIN
2. DKK1
- Both inhibit osteoblast differentiation
- They bind to the LRP5/6 to prevent it forming a complex with the Fz receptor. The FZ receptor is inactive without the formation of a complex, so there's no Wnt signaling & therefore no downstream osteoblast differentiation
33
How do osteocytes act as key regulators of bone remodelling?
- Osteocytes produce RANKL, OPG, SCLEROSTIN & DKK1
| - During bone formation, osteocytes control the expression of sclerostin & dkk1 to control osteoblast differentiation
34
What is osteoporosis?
- Osteoporosis refers to a loss of trabecular bone resulting in weak, fragile bones. (Porous bones - bone loss)
- It is defined as having a bone mass of greater than 2.5 SD below the average bone mass
- Can be due primary (menopause, aging) or secondary (lifestyle, drugs etc.)
35
Why does the risk of osteoporosis increase with age?
- Peak bone mass is reached at 20 years, it then begins to decline thereafter every year
- Menopause leads to a drop in oestrogen levels. The sudden drop in oestrogen stimulates osteoclast differentiation leading to bone loss, until the body adapts to the low oestrogen
36
What is osteopetrosis?
- Osteopetrosis/osteosclerosis refers to an abnormal increase in bone mass where the trabecular bone is thicker
37
Give two possible causes of Osteopetrosis?
1. LRP5 ACTIVATING MUTATIONS
| 2. VAN BUCHEM'S DISEASE
38
How can LRP5 activating mutations cause osteoporosis?
- LRP5 activating mutations mean that the Wnt signalling pathway will be continuously active as the LRP5 will always be in complex with the Fz receptor
- Continuous activation of the Wnt signalling pathway means that there is increased osteoblast differentiation leading to excess bone formation
39
How can Van Buchem's lead to osteoporosis?
- Van Buchem's is a rare inherited disorder where there's a loss of function for the SOST gene.
- The SOST gene codes fro the protein Sclerostin, so without it Sclerostin won't be produced
- As sclerostin inhibits osteoblast differentiation, there will be reduced inhibition if it isn't produced
- Excess osteoblast differentiation leads to excess bone formation
