Physiology Of Bone And CT Flashcards
Key elements of bones
Large amounts of ECM w/ proteins and hydroxyapatite crystals.
Also contain Progenitor cells, osteocytes, blasts and clasts which continue to remodel bone as needed.
- matrix is key provider of strength and stability
Connective tissue cells
Fibroblast, immigrant and resident chondrocytes, macrophages, mast cells and plasma cells.
Pyrophosphate
Inhibits spontaneous hydroxyapatite formation since the concentration of calcium and phosphate ions naturally well exceed the required amount to cause spontaneous formation.
Found in all normal tissues and plasma, except for bone.
% of nutrients bone contains
99% of entire body calcium and phosphate
80% of entire body carbonate
50% of entire body magnesium
35% of entire body sodium
33%/67% ratio of organic:inorganic compounds in bone composition.
Bisphosphonates
Used to combat loss of bone.
Contains high phosphate concentration which promotes hydroxyapatite formation and also encourages osteocytes apoptosis.
Organic 33% of bone consists of what?
28% collagen
5% proteins (non collagen)
67% of inorganic bone composition consists of what?
Primarily hydroxyapatite
What vitamin deficiency causes collagen formation deficiencies?
Vitamin C
Removing organic vs inorganic matrix of bones.
Remove organic = brittle bones (shatter easily)
Remove inorganic = twisty bones (cant resist compression)
Summary of 4 types of bone cells
Progenitor osteocytes: stem cells who differentiate into osteoblasts
Osteoblasts: immature bone cell that secretes osteoid.
Osteoclast: multinucleated cell differentiated from osteoblasts that dissolve hydroxyapatite via acidic molecules
Osteocyte: mature bone cell that maintains bone matrix
RUNX2 gene defects
Defective Gene that inhibits preosteoblast proliferation and differentiation ultimately reducing the total amount of osteoblasts.
- causes lack ossification in teeth and bones, especially the collarbones
(Cleidocranial dysplasia)
Osx (Sp7)gene deficiency
Inhibits osteoblasts and osteocytes maturation and differentiation from preosteoblasts
Secrete poor osteoid that makes mineralization difficult and collagen synthesis poor.
Deficiencies lead to osteogenesis imperfecta (brittle bone disease)
Integrins
Integrins: bind vitronectins on bone surfaces to seal osteoclasts to bone
Vitronectins
Surface proteins that bind to integrins on bone to stabilize osteoclast for bone reabsorption.
Acid proteases and protons
Secreted in the vesicular zone right above the ruffled border of the osteoclast. Are released into the bone and cause break down of hydroxyapatite into Ca2+ and PO4
V-type proton pump and ClC7 channels
Channels and pumps that are located at the ruffled border that help initiate exocytosis of H+ ions and proteases.
Use ATP so is a form of active transport against the proton gradient
Carbonic anhydrase
Supplies the H+ ions in the osteoclast.
Gets protons from water and generates bicarbonate from OH + CO2. Bicarbonate is excreted via Cl-HCO3 pumps
CL-HCO3 exchangers
Antiport that pumps chloride in and bicarbonate out. Helps get chloride into the cell to secrete with protons into the howship lacuna
Clathrin
Mediates formation of secretory vesicles in vesicular zone.
Helps bind the vesicles to the correct area.
Tartrate-resistant Acid phosphatase (TRAP)
Metalloenzyme expressed in osteoclasts and macrophages
Staining of this enzyme is often done to determine osteoclast activity.
Factors that must be expressed for Mesenchymal cells to differentiate into osteoblasts
Cbfa1/Runx2 and Osx
Primary (woven)bone
First bone formed at any site and contains random fiber orientations.
-ultimately replaced by lamellar bone with parallel fibers.
Purposes of bone remodeling
Establish optimum bone strength
Repair damaged bone
Maintain calcium homeostasis
RANKL
receptor activator of KB-nf ligand
Expressed by osteoblasts and helps control osteoclast activity and formation.
RANK
Receptors themselves for RANKL
Located on osteoclast precursors and mature osteoclasts
OPG
Osteoprotegerin
Binds to and inhibits RANKL
Expressed by osteoblasts and other body tissues
Prevents bone loss
RANKL/RANK/OPG pathway
Osteoblasts release RANKL wither by itself or in conjunction with OPG
By itself: will bind to RANK receptors on osteoclasts and/or osteoclasts precursors.
Initiate differentiation to mature osteoclasts. And activates bone reabsorption.
Together w/ OPG: OPG binds to RANKL and inhibits it from binding to RANK.
Estrogen (estradiol) vs menopause
Hormone that can limit release of RANKL. High estrogen increases OPG production as well and both increase bone production
Menopause (low estrogen) increases RANKL production and causes bone reabsorption.
RANKL/RANK uses other than bone remodeling
- High RANKL levels have been indicative of increased progesterone release and also the regulation of BRCA1 mutation for breast cancer.
- lactation in mammary glands occurs via RANKL/RANK pathway
- Dendritic cell production and maturation occurs in part due to RANK/RANKL pathway.
Denosumab
Antibody that acts similar to OPG and inhibits RANKL binding to RANK receptors.
used in treatment of osteoporosis.
Calcitonin vs PTH
Calcitonin: Tends to decrease plasma calcium and antagonize PTH
PTH: tends into increase plasma calcium and antagonize calcitonin.
- PTYH also lowers OPG levels.
Protein Kinase A
Inhibits bone resorption in osteoclasts in high levels.
Is formed via cAMP and adenylyl Cyclase via calcitonin binding
IL-6
Believed to play a role in up regulating RANKL production leading to overall increases in bone resorption
M-CSF (macrophage colony stimulating factor)
Released with RANKL and binds to preosteoclasts stimulating a tyrosine kinase pathway for differentiation
Initiates differentiation from preosteoclasts -> mature osteoclasts.
WNT/(b)-catenin pathway
WNT is produced by osteoprogenitor cells and binds to LRP5 and 6 receptors on osteoblasts.
This causes osteoblasts to release (b)-catenin which stimulates production of OPG
Ultimately reduces osteoclast activity.
Sclerostin
Produced by osteocytes and inhibits the WNT/(b)-catenin pathway.
Decreases OPG secretion and increases osteoclast activity.
BMPs
Bind to transmembrane serine and threonine receptors and induce heterotropic bone formation
- ectopic cartilage formation followed by Endochondral bone. (Often proceeds major trauma)
- increase osteoblast activity.
PTH (84)
Secreted by parathyroid and is metabolized into active PTH (34) and inactive PTH (84)
Actions of activated PTH throughout body
Blood:
- increase and decrease serum calcium and phosphate respectively.
Kidney:
- cAMP, active Vitamin D and kidney absorption of urine Ca are increased.
- Urine phosphate absorption is decreased
Bone
- osteoclast and osteoblast activity are increased.
Chief cells
Primary cells of Parathyroid that secrete PTH
Oxyphil cells
Unknown function but are thought to be modified or deprecated chief cells.
Synthesis and secretion of calcitonin occur in what cells of the thyroid?
Parafollecular cells (C cells)
calcitonin is also a 32 amino acid peptide that is always released in active form
Normal Ca2+ blood concentration
10mg/dl
<10mg = increased PTH secretion, decreased PTH
> 10mg = increased calcitonin secretion, decreased PTH
Calcitriol
Hormone in intestines and kidneys that stimulate calcium reabsorption in digestive renal tract.
Regulators of phosphate homeostasis
PTH (parathyroid cheif cells)
Active 1,25 vitamin D: (renal cells)
FGF23 (released by osteocytes
All reduce phosphate reabsorption / increase urination excretion of phosphate
Vitamin D specific causes of rickets and osteomalacia
Deficiency in Vitamin D causes poor absorption of calcium in intestines and kidneys.
Leads to increased PTH secretion which ultimately increases osteoclast activity
Also leads to inhibition of phosphate ion reabsorption = cant make hydroxyapatite.
- leads to defective hardening of bones (Soft bones and abnormal long bones)
Rickets = kids ; osteomalacia = adults
Testosterone
Increase bone deposition/ growth
Compression vs tensions vs pressure on bones
Compression = stimulates bone deposition/growth
Tension =. Stimulates bone deposition/growth
Pressure = sitmulates bone resorption/ breakdown
Special CT subcategories
Adipose, cartilage, bone and bone marrow
Embryonic Connective Tissue
Mesenchyme
LRP5 & 6 receptors
Receptors on osteoblasts that receive signals from
BMP, Sclerostin, WNT.
Sclerostin = decreases (b)-catenin secretion and INHIBITS osteoblasts
WNT & BMP increases (b)-cateinin secretion and PROMOTES osteoblasts
Albumin
Binds calcium and fatty acids found in plasma
Low ionized calcium binds best to albumin
