Bone homeostasis Flashcards
What are the 2 main mineral components of bone
Calcium and phosphorus
What is the biologically active form of Ca
the ionized calcium
What is the chemical gradient for Ca
10,000:1
Symptoms of hypocalcemia
nervous system is more excitable. hyper excitability because threshold for Na channels drops
tetany
Symptoms of hypercalcemia
decreased QT interval of the heart, lack of appetite and constipation. reflex responses are slowed
What is the range for Ca
8.5-10.5 mg/dL
What triggers release of PTH
low levels of serum Ca
What are the 4 functions of PTH
1) PTH R on osteoblasts trigger initiation of bone resoprtion leading to release of Ca into serum
2-3) regulates Ca retention and phosphate excretion in kidney
4) increase 1,25(OH)2D3 synthesis–> increase Ca absorption from GI
Unregulated release of PTH leads to what and why
hypercalcemia because PTH increases Ca absorption in gut and resorption via osteoblasts/clasts
What cells produce calcitonin and in what response
C cell sin thyroid gland produce calcitonin when there is an increase of serum Ca
How do calcitonin levels change in individuals with medullary thyroid cancer
increase calcitonin levels
When is calcitonin used therapeutically
bone disorders characterized by excessive bone resorption
Where in the body is Vit D converted to its active form
in the kidney
What is Calcitriol (1,25 (OH2)D3) necessary for
absorption of Ca from GI, bone formation and promotes Ca and Pi resorption from kidney
What happens in a Vit D deficiency
impaired Ca absorption and poor mineralization of bone
What mineral does FGF23 regulate
phosphate
FGF23 knockout mice presented how
hyperphosphatemia and hypercalcemia due to increased levels of calcitriol
What percent of bone is minerals
70%
Majority of organic bone matrix is what
collagen type I
4 amino acids to make up collagen type I matrix
glycine, alanine, proline and 4-hydroxyproline
collagen structure
Right handed helix of three left handed helices
What is the most necessary aa in collagen
glycine because it is so small and links everything
Cleavage for collagen FORMATION creates what byproducts- used how clinically?
PINP and PICP peptides
used as a marker for collagen formation
What cross links the tropocollagen in bone, and what co-component is needed
pyridinoline molecules
needs Asorbic Acid(Vit C)
Symptoms of scurvy
small hemorrhages caused by fragile blood vessels, tooth loss, poor wound healing and the reopening of old wounds, bone pain and heart failure
What are the byproducts of collagen degradation and how are they used clinically?
pyridinoline, deoxypiridinoline, N telopeptides and C telopeptides.
measured in serum and urine to measure collagen breakdown
What is in inorganic bone matrix
Ca and phosphate ions that make hydroxyapatite crystals
Components of bone
Osteon, lacunae, lamellar bone, canaliculi
osteoid
Are bone resorption and formation coupled during bone modeling during puberty
no uncoupled– net bone formation
Is bone remodeling coupled or uncoupled
coupled so that there is no net formation of bone
Osteoblasts are derived from what cell lineage
mesenchymal stem cells
What is the job of osteoblasts
lay down collagen and noncollagen proteins BEFORE mineralization
Why is mineralization delayed for several days
so collagen can cross link
What happens to the osteoblasts that become trapped in the cellular matrix
become osteocytes and cellular processes that lie in canaliculi to connect osteocytes to osteoblasts
What conneciton allows for the communication of mechanical stress in bone to be heard on surface
the canaliculi and osteocytes
What are the markers for bone formation
alkaline phosphatase and osteocalcin
How are osteoblasts and osteoclast so connected
osteoblasts signal for osteoclast activation
Osteoclasts are derived form what cell lineage
hematopoietic stem cells
What hormone inhibits osteoclasts
Calcitonin
When osteoblasts are stimulated by PTH what do they secrete
M-CSF
RANK Ligand
osteoptrotegerin
What responds to RANK Ligand
osteoclasts. stimulates them. have RANK receptor
What is the role of osteoprotegerin
soluble Receptor for RANKL- inhibits its binding to osteoclasts
Diseases of hyperactive and chaotic bone deposition result in stronger or weaker bones
weaker
4 steps of bone remodeling
activation, resorption, reversal and formation
Why do bones get more frail as we age
uncoupled bone resorption and formation. usually net bone resorption
How is PTH used therapeutically
used intermittently to activate osteoblasts without then activating osteoclasts
What systemic hormones have a positive influence on bone formation
growth hormone, thyroid hormone, insulin, and gonadal hormones
What effect do gluccocorticoids have on bone formation
suppress bone formation. suppress intestinal Ca absorption and induce osteoclastogenesis
also deplete osteoblasts through suppression of differentiation factors and induction of apoptosis
What gonadal hormones influence bone homeostasis
estrogen and androgens
Estrogen is needed for what specific event in bone growth
closure of epiphyseal plates
estrogen deficiency results in
loss of bone mass
Local regulators of bone homeostasis
Cytokines IL1 TNFa TNFb and IL6 increased bone resorption
prostaglandins stimulate bone resorption
What growth factors have effects on bone
FGF, PDGF, Insulin-like GF and bone morphogenetic proteins
DEXA SCAN is used to measure what, what is the criteria
bone density
T > -1 is normal
T under -2.5 osteoporosis
What is measured in serum to measure bone formation
alkaline phosphatase
osteocalcin
PINP and PICP peptides
What is the role of osteocalcin
osteoblasts release osteocalcin
What is measured to measure bone resorption
urinary hydroxyproline
NTx and CTX telopeptides
Most common metabolic bone disease
osteoporosis
nonmodifiable risk factors for osteoporosis
Age, race, gender, menopause, build and family Hx
modifiable risk factors for osteoporosis
Ca intake, Vit D intake, Estrogen supp, sedentary lifestyle, smoking, alcohol excess, caffeine excess and medications
Post menopausal women have primary or secondary osteoporosis
primary
2 examples of secondary osteoporosis
gluccocorticoid excess and hypogonadism
What pharmacological agents are used to treat osteoporosis
antiresorptive (bisphosphonates) and anabolic intermittent injections of PTH
Rickets and osteomalacia are characterized by what type of disorder
mineralization of organic matrix.
usually Vit D deficient
also hypophosphatemia and alkaline phosphatase deficient
Classification levels for Vit D deficiency
severe 0-10
moderate 10-20
mild 20-30
greater than 30 is normal (ng/ml)
What disease is characterized by excessive osteoblastic activity and hyperactive bone remodeling
Paget’s disease
Symptoms of Pagets
usually none. can have bone pain, deformity, fracture, and arthritis
Tx of Pagets
bisphosphanates
3 phases of Pagets
1) osteolytic- excessive osteoclastic activity
2) mixed phase osteoclast and osteoblast activity
3) osteosclerotic phase- predominance of osteoblast activity and sclerosis
The third phase of pagets is diagnosed based on what
extremely elevated alkaline phosphatase levels
What is the brittle bone disease
osteogenesis imperfecta, mutations in collagen
Most common type of Osteogenesis Imperfecta
type I- most common 80% cases.
autosomal dominant
one allele of alpha1 pro collagen gene is missing
decreased collagen formation but normal structure
symptoms of OI type I
bone fragility, short stature, blue sclerae, joint laxity and hearing loss
What type of OI is characterized by osteopenia of long bones and wormian bones of skull
type I
OI type II
severe. point mutation of COL1A1
extreme bone fragility usually death intrauterine
OI type III
like type II but less severe. skeletal deformities
OI type IV
milder phenotype similar to type I
Osteopetrosis
marble bone disease, genetic mutations
What is defective in ostepetrosis
osteoclastic bone resorption resulting in disorganized bone structure
Mech of bisphosphonates
selectively taken up by the bone and inhibit osteoclast activation, inhibiting bone resorption
mechanism of prolia
monoclonal ab against RANK Ligand. inhibits bone resorption
