Physiology Of Bone Flashcards
What are the main physiological functions of bone tissue?
Support, movement, protection, mineral storage, blood cell formation, energy storage and energy metabolism
What do the organic components and especially collagen contribute to bone tissue?
The flexibility and tensile strength that allow bone to resist stretching and twisting
What are the organic components of bone ECM?
Osteonectin, osteocalcin, proteoglycans, sialoproteins, osteopontin and thrombospondin
What is the function of osteonectin and osteocalcin in organic bone ECM?
Aid in hydroxyapatite crystallization and bind Ca
What is the function of proteoglycans in organic bone ECM?
Bind growth factors (ex. TGF-beta)
What is the function of sialoproteins, osteopontin and thrombospondin in organic bone ECM?
Mediate osteoclast adhesion to bone surface (bind osteoclast integrins)
What are the inorganic components of bone ECM?
Hydroxyapatite or mineral salts primarily Ca phosphate (some Ca carbonate, K and Mg)
What is the function of the inorganic component of bone ECM?
Present as tiny crystals to line and around collagen fibrils in ECM
Pack tightly contributing to hardness and ability to resist compression
What are osteogenic cells?
Stem cells that differentiate into bone forming osteoblasts
Where are osteogenic cells located?
Within the deep/inner layer of periosteum and the marrow
What are osteoblasts?
Cuboidal shaped cells derived from mesenchymal stem cells
What do osteoblasts directly regulate?
Bone matrix synthesis and mineralization
What do osteoblasts indirectly control?
Bone resorption through release of paracrine factors that regulate osteoclasts (RANKL/OPG)
What can osteoblasts become?
Osteocytes embedded in the matrix
Bone lining cells which protect inactive bone surfaces
Or will die by apoptosis
What are osteocytes?
Terminally differentiated osteoblasts but smaller in size and contain projections that branch into the matrix
Where as osteoblasts located?
Growing portions of bone including periosteum and endosteum
Where are osteocytes located?
Trapped within newly deposed bone matrix
What is the function of osteocytes?
Respond to mechanical loading by releasing paracrine factors
Stimulate and coordinate bone remodeling and Ca release from the matrix
What are osteoclasts?
Specialized multinucleated cells derived from mononuclear cells in the bone marrow
Resorb mineralized bone matrix by secreting acid and lytic enzymes
What is osteoclast differentiation controlled by?
Receptor activation of nuclear factor kB (RANKL) from osteoblasts
Can be inhibited by OPG which sequesters RANKL
Where are osteoclasts located?
Bone surfaces and site of old or injured bone matrix
What does Wolff’s law state?
That your bones will adapt based on the stress or demands placed on them
When you work your muscles, they put stress on your bones and in response your bone tissue remodels and becomes stronger
What is the purpose of bone remodeling?
Repairs micro damage, maintains bone strength and maintains serum Ca levels within normal physiological ranges
Regulation of bone remodeling and modeling is through a number of what?
Local and systemic regulators including TGF-beta, BMPs, OPG, FGFs, IGFs, PDGF, interleukins and PTH
What function does TGF-beta play during bone remodeling?
Stimulates the proliferation and differentiation of osteoblasts and bone formation
Increases OPG production
What function do BMPs play during bone remodeling?
Potent inducers of osteoblasts and bone formation
Regulate matrix production
How are BMPs used clinically?
rhBMP-2 is used in fracture healing/spinal fusion
What function does osteoprotegerin (OPG) play during bone remodeling?
Secreted from osteoblasts and bind to RANKL to prevent osteoclast activation (aka prevents bone resorption)
What function do FGFs play during bone remodeling?
Increase proliferation of osteoblasts
Enhance callus formation during fracture repair
What does FGF-2 stimulate during bone remodeling?
Angiogenesis during fracture repair
What function do insulin like growth factors (IGFs) play during bone remodeling?
Stimulated by growth hormone and increase bone collagen matrix synthesis
Also inhibits degradation
What function does platelet derived growth factor (PDGF) play during bone remodeling?
Increase collagen synthesis
What function does RANKL play during bone remodeling?
Secreted from osteoblasts
Activates osteoclasts for bone resorption
What is RANKL regulated by?
OPG
What function do interleukins play during bone remodeling?
Stimulate bone resorption
IL-1 is the most potent
IL-1 expression is decreased by what?
Estrogen which is a possible mechanism for post-menopausal bone resorption increases
What function does PTH play during bone remodeling?**
Falling blood Ca (Hypocalcemia) signals parathyroid glands to release PTH which signals osteoclasts to degrade bone matrix and release Ca into the blood
Fracture healing is what?
A specialized type of wound healing involving inflammation, repair and remodeling
The healing sequence of fracture repair depends on what?
Movement between fragments
Limited movement = indirect bone healing
No movement = direct bone healing
What are the 5 stages of indirect (secondary) fracture healing?
- Tissue destruction and hematoma formation
- Inflammatory phase which stimulates blood vessel formation and recruitment of mesenchymal cells
- Soft callus formation (made up of fibrous CT and helps restrict fragment movement)
- Hard callus formation (woven -> lamellar bone)
- Remodeling of bone
Inflammatory phase of indirect fracture healing occurs when?
Week 1
Soft callus formation phase of indirect fracture healing occurs when?
Weeks 2-3
Hard callus formation phase of indirect fracture healing occurs when?
Weeks 4-12
Bone remodeling phase of indirect fracture healing occurs when?
For years
Describe direct (primary) fracture healing
Contact healing between bones
No callus is formed
Requires absolute stability between fracture fragments (no motion)
What is contact healing in direct fracture healing?
Direct contact between bone fragments ends (lamellar bone)
When there is a gap between bone fragments that is 200-500nm wide what will occur with direct fracture healing?
Woven —> lamellar bone
When there is a gap between bone fragments that is 500nm wide what will occur with fracture healing?
Indirect healing will occur
What are examples of anti-resorption treatments?
Bishophophonates, hormone replacement (estrogen, selective estrogen receptor modulators or denosumab
How are bisphosphonates used as an anti-resorption agent?
They inhibit osteoclast activity and induce osteoclast apoptosis
What is denosumab and how is it used as an anti-resorption agent?
It is a monoclonal Ab against RANKL
What are examples of anabolic therapeutic agents?
BMP2 and PTH
How does BMP2 function as an anabolic therapeutic agent?
Induces osteoblast proliferation and activity for increased bone matrix production
How is PTH used as an anabolic therapeutic agent?
Intermittent (daily) administration is anabolic with reductions in vertebral fractures of up to 70% being reported over untreated pts
Mechanism is unclear
Continual administration of PTH is what?
Catabolic for bone with increased osteoclast formation due to changes in expression of OPG and RANKL by osteoblasts
What are examples of endocrine regulation of bone metabolism?
Estrogen, thyroid hormones, glucocorticoids, PTH and growth hormone
Explain how estrogen is an example of an endocrine regulator of bone metabolism
Stimulates fracture healing through receptor mediated mechanisms
Decrease RANKL production from osteoblasts
Modulates release of specific inhibitor of IL-1
Explain how thyroid hormones are an example of an endocrine regulator of bone metabolism
Thyroxine and T3 stimulate osteoclastic bone resorption
Explain how glucocorticoids are an example of an endocrine regulator of bone metabolism
Inhibit Ca absorption from the gut causing increased PTH and therefore increased orthroclastic bone restoration
Explain how PTH is an example of an endocrine regulator of bone metabolism*
Intermittent exposure stimulates osteoblasts and increases bone formation
More chronic exposure or pathological levels (hyperparathryoid) stimulates osteoclasts to release Ca and can lead to hypercalcemia
Explain how growth hormone is an example of an endocrine regulator of bone metabolism
Mediated through IGF-1
Increases callus formation and fracture strength by stimulating osteoblasts
