Exam 2- Bone Flashcards
1
Q
Function of bone (3)
A
- structural support and protection
- hematopoiesis (formation of immune cells)
- mineral storage
2
Q
Inorganic component of bone
A
- hydroxyapatite
3
Q
Calcium’s role in the body (3)
A
- neurotransmitter release-
- muscle contraction
- coagulation
4
Q
Phosphate’s role in the body (3)
A
- ATP, DNA, RNA
- cellular signaling (kinase cascades)
- Phospholipids
5
Q
Bone Architecture: 2 types
A
- long bone
- vertebral bones and in the neck/head of femur
6
Q
Long bone
A
- cortex and medulla
- cortex: forms thick outer layer
- medulla: trabecular bone (ends, spongy) and bone marrow
7
Q
Vertebral bones and in the neck/head of femur
A
- cortical bone forms a thinner layer surrounding a larger core of trabecular bone
8
Q
most remodeling is in which part of the bone?
A
- trabecular (almost exclusively)
9
Q
Bone composition
A
- 75% inorganic components (primarily hydroxyapatite)
- 99% of the body’s calcium is stored in skeleton
- 25% organic components
10
Q
Organic components of bone
A
- Cells (osteoblasts, osteoclasts, osteocytes) (bone lining cells)
- Osteoid (matrix consisting primarily of type I collagen fibers; other low-abundance proteins)
- Growth factors (as you break down bone, growth factor is released)
11
Q
Average daily intake of Ca vs absorption and what is done with the balance
A
- daily intake 1000mg
- 300 mg dietary Ca normally absorbed
- balance excreted in feces and urine
12
Q
Calcium is absorbed where and how transported?
A
- Small intestine
- facilitated transport throughout small intestine
- Vitamin D dependent transport mainly in duodenum
13
Q
If defects/deficiencies in Vitamin D, what happens to Ca?
A
- not enough is absorbed
14
Q
Calcium absorption can be increased to 600 mg/day by ______
A
- calcitrol (active form vit D)
15
Q
% of trabecular and cortical bone remodeled each year in adults? What does this mean in regards to deficiencies in calcium?
A
- 25% of trabecular bone remodeled each year
- 3% of cortical bone
- If there is a deficit, within a year will see deficiency in density of bone
16
Q
pathological conditions preferentially affect bones with high content of ______
A
- trabecular bone
- ex femoral neck and vertebral bodies
17
Q
osteocytes’ job
A
- sense stress, regulate activity of osteoclasts and osteoblasts (slide 19)
18
Q
Bone Resorption
A
- physical or chemical signals recruit osteoclasts
- excavate small cavities on surface of bone
- extend villus-like projections towards bone surface that secrete proteolytic enzymes that digest the organic matrix
- create an acidic microenviron by producing organic acids (H/ATPase pump on surface of villi) which dissolves hydroxyapatite
- lasts about three weeks which at that point cytokines and other factors are liberated from the matrix to stim bone formation
19
Q
Bone Formation
A
- osteoblasts replace osteoclasts in the resorption cavity
- begin to refill the cavity with concentric layers of unmineralized organic matrix (osteoid/lamellae)
- eventually the osteoblasts become completely surrounded with matrix –> become osteocytes
- osteocytes act as mechanosensors in bone
- Osteoblasts secrete factors for mineralization
- Alkaline phosphatase
- Calcium-binding proteins
20
Q
What does alkaline phosphatase do in the process of bone formation?
A
- hydrolyzes various phosphate esters including pyrophosphate which is an inhibitor of bone mineralization
- promotes crystallization of calcium phosphate salts
21
Q
What do calcium-binding proteins do for bone formation?
A
- increase local concentration of calcium
- facilitates hydroxyapatite formation
22
Q
Parathyroid hormone and it’s secretion
A
- secreted by parathyroid glands
- most important endocrine regulator of calcium homeostasis
- secretion regulated by plasma calcium levels
- calcium-sensing membrane receptors of chief cells in Parathyroid gland
- GPCRs cause increased intracellular free calcium
- Increased intracellular calcium levels DECREASES secretion of preformed PTH
- decreased intracellular calcium levels INCREASES secretion of preformed PTH
- this is opposite of most secretory systems
23
Q
PTH receptor Activation (two main types/groups of receptors and where they are expressed)
A
- PTH/PTHrP receptor
- responds to PTH and PTH-related protein
- expressed high levels in kidneys and osteoBLASTS
- activates several G proteins
- PTH2 receptor
- activated by PTH but not PTHrP
- expressed in brain, vascular endothelium, smooth muscle, GI endocrine cells, sperm
- functional role is unknown
24
Q
Effects of PTH on kidney
A
- Direct
- most rapid physiological effects of PTH
- increases reabsorption of calcium by kidney (decreases urinary excretion)
- Decrease reabsorption of phosphate by kidney (increases urinary excretion)
- PTH raises plasma calcium levels and decreases plasma phosphate concentrations
25
Effects of PTH on bone
- Direct
- slower effect of PTH than kidney
- physiologic levels of PTH stim cell surface PTH receptors on osteoBLASTS
* causes increased expression of RANK-L
- liberates calcium and phosphate by osteoclastic activity
- raises plasma calcium levels
26
What does RANK-L do?
- RANK-L is expressed on osteoBLASTS and binds to RANK on osteoCLAST precursor cells in bone marrow
- this binding promotes differentiation into mature osteoCLASTS
- this then liberates calcium and phosphate by osteoclastic activity
27
Effects of PTH on GI tract
- INDIRECT
- PTH stims kidney which increases formation of calcitriol
* hydroxylation step occurs in cells of proximal tubule
- calcitriol increases calcium absorption in the small intestine
28
Anabolic Actions of PTH
- brief 1-2 hr exposure of PTH
- increases bone formation and bone mass
- enhances osteoblast survival and promotes osteoblast differentiation
- Galphas receptor stimulation by mature osteoBLASTS increases cAMP which has an anti-apoptotic effect on osteoblasts and promotes osteoblasts IGF-1 release inducing osteoblast differentiation
- PTH also induces production of cytokines by stromal cells which stims osteoCLAST production
- but acutely osteoBLAST effect dominates
29
Catabolic Actions of PTH
- continuous exposure to PTH
- mature osteoblasts stim production of IGF-binding proteins which decrease IGF-1 levels and osteoblast differentiation
- PTH induces expression of osteoclast differentiation factors
- net result is osteoCLASTS outnumber osteoBLASTS
30
Vitamin D
- produced in sufficient amts by the body (not usually needed through diet)
- Vit D applies to 2 related compounds (equal biological activities)
* Cholecalciferol (Vit D3): synthed by skin from exposure to UV radiation
* Ergocalciferol (Vit D2): form produced by plants, what is present in many commerical preps and added to milk
31
Calcitriol biosynthesis
- active form of Vit D
- Vit D2 and D3 travel to liver where it is stored or converted to calcifediol
- two enzymatic hydroxylation steps to form calcitriol (second hydroxylation is PTH-dependent and in proximal tubule of kidney)
32
Calcitriol: What it do
- increases absorption of dietary Ca
- acts on nuclear receptors in the enterocytes
- up-regulates gene expression of certain Ca pumps and Ca binding proteins (calbindin)
- inhibits PTH synth and release from parathyroid gland
- increases osteoclast number and activity in bone
- calcitriol affects distal tubule of kidney to increase reabsorption of both calcium and phosphate
- macrophages can produce calcitriol
* may act as a local suppressant of adaptive immune cells
33
What can you use to treat psoriasis?
- Vit D
34
Calcitonin
- produced and released by parafollicular C cells of thyroid gland
- released in response to HYPERcalcemia
- effects: binds directly to receptors on osteoCLASTS and inhibits the resorptive activity --> decreases bone resorption and plasma calcium levels
- In adult humans: only weak effect of endogenous calcitonin on plasma calcium levels
- thyroidectomy generally doesn't cause any significant changes in plasma calcium levels
- exogenous calcitonin used in treatment of osteoporosis
35
Glucocorticoids and effect on bone processes
- decreases intestinal absorption and tubular reabsorption of calcium, but NOT associated with hypocalcemia
- compensatory increase in PTH
- glucocorticoid effects on bone
* inhibit osteoBLAST maturation
* inhibit osteoBLAST activity
* promotes osteoBLAST apoptosis
- prolonged administration causes iatrogenic osteoporosis
36
Thyroid hormone effect on bone processes
- excess hormone increases bone turnover
- stimulates bone resorption more than bone formation
- prolonged elevated levels causes osteopenia
37
Estrogens and androgens effect on bone processes
- exert inhibitory effects on osteoCLASTIC activity
- slow rate of bone turnover and bone loss
- gonadal steroids inhibit the production of cytokines by osteoblasts (IL-6 normally recruits and activates osteoCLASTS
- estrogen has pro-apoptotic effect on osteoclasts, anti-apoptotic effect on osteoblasts and osteocytes
38
Osteoporosis general considerations and vs osteopenia
- osteoporosis: decreased production of bone matrix and decreased BMD
- Normal BMD: value within 1 SD of the mean BMD in young adults
- Osteopenia: 1-2.5 SDs below the mean
- Osteoporosis: >2.5 SDs below the mean
* leads to increased risk of fracture from minimal trauma
* esp vertebrae, femoral neck (hip), and radius (Colles' fracture)
39
Two categories of osteoporosis (list)
- Primary (Senile and Post-menopausal)
| - Secondary (systemic illness and medications induced)
40
Senile Osteoporosis
- peak bone mass achieved in young adulthood
- determined by several factors: dietary calcium, Hormonal state, physical activity levels, genetic factors
- gradual decline in bone mass during mid- late adult life
- osteoblast-mediated bone formation declines in relation to osteoclast activity
- average loss of 0.7% bone mass / year
41
Postmenopausal Osteoporosis
- begins in first 3-5 yrs after menopause
- RAPID loss in bone mass related to marked decline in estrogen production
- longer lifespan in osteoCLASTS in absence of estrogen
- excavate deeper cavities which coalesce to form porous spaces in cortical bone
- increased apoptosis of osteoblasts
- increased apoptosis of osteocytes impairing mechanosensory network
- within 25-35 yrs after menopause
* 35% of cortical bone mass loss possible
* 50% of trabecular bone mass loss possible
42
Secondary Osteoporosis
- systemic illnesses and medication-induced
- common predisposing causes: Thyrotoxicosis, hyperparathyroidism, high doses glucocorticoids, smoking, alcohol abuse
- treat UNDERLYING cause
43
How does CKD affect bone mineral homeostasis?
- mainly through secondary hyperparathyroidism which enhances resorption of bone
- bones develop osteomalacia (decreased mineralization) and osteitis fibrosa cystica (increased osteoclastic resorption of bone with replacement by fibrous tissue)
44
Hyperparathyroidism and CKD
- decreased production of Calcitriol b/c impaired hydroxylation step in kidneys
- results in HYPOcalcemia
- results in HYPERphosphatemia (impairment of renal tubular function)
45
Effects of low calcitriol with CKD
- leads to inadequate intestinal absorption of calcium which leads to hypocalcemia
- this stims PTH secretion and suppresses PTH degradation
- reduces Ca receptor synth in chief cells of parathyroid gland which raises set point for Ca regulation (higher [Ca} required to suppress PTH)
- hyperparathyroidism can persist even with hypercalcemia
- low Ca levels cause SECONDARY hyperparathyroidism
- Calcitriol also normally suppresses growth of the parathyroid gland and suppresses transcription of the PTH gene
- HYPERphosphatemia results from the decreased renal excretion of phosphate, exacerbates the hypocalcemia, alters the equilib for hydroxyapatite formatino and dissolution
46
Therapeutic treatment for CKD
- active Vit D analogues (bypass hydroxylation requirement by kidneys)
- calcimimetic cinacalcet (adjusts sensitivity of calcium-sensing receptor on parathyroid chief cells)
