Biochemistry Of Bone Metabolism

Question 1

Bone homeostasis biochemistry brief overview

Answer 1

Bone matrix = collagen and hydroxyapatite

Osteoblasts = grow and lay bone

Osteoclasts = destroy bone via RANKL signaling and kinase cascades

Bone grows from hydroxyapatite crystals

4 phases

1) osteoclast resorption
2) osteoblast activation and matrix formation
3) mineralization
4) resting phase
* *all 4 phases in one movement takes 160-200 days**

Question 2

How is calcium and phosphate moved in and about of bone by osteoclasts?

Answer 2

Requires facilitated transport channels since osteoblasts have strong tight junctions

Phosphate is also actively produced by secretion of phosphate contains compounds (including ATP)

Question 3

How does hydroxyapatite form?

Answer 3

From the combination of phosphate, calcium and water at a slightly alkaline pH
- however as hydroxyapatite crystals precipitate, there is release of H+ ions forming acid which rapidly lowers the pH and prevents excess hydroxyapatite crystal formation

the acid is removed in unknown mechanism, however to remove hydroxyapatite, osteoclasts pump H+ ions into the bone area

Question 4

Parathyroid hormone and bone regulation

Answer 4

PTH is produced by chief cells in the parathyroid glands

Actions

• increase cAMP in DCTs of renal cells to promote reabsorption of calcium
• activates PCT cells to increase activation of Vitamin D activity (1,25)
• decrease phosphate reabsorption
• increase osteoclast and osteoblast activity
• increases serum calcium and decreases serum phosphate

Question 5

What is the pathway of vitamin D activation

Answer 5

1) 7-dehydrocholesterol -> cholecalciferol from UV light
2) cholecalciferol -> vitamin D3 (25-OH-D3) in the liver from 25-hydroxylase enzymes

3) 25-OH-D3 -> 1,25 -diOH in the kidney via the enzyme 1-hydroxylase
- 1,25-diOH has a negative feedback on 1-hydroxaylase

4) 1,25-diOH -> intestines to bind to calbindin proteins or just floats around in the blood

Question 6

How does PTH affect osteoclasts and osteoblasts

Answer 6

PTH binds to PTH1R and PTH2R

PTH1R = on both clasts and blasts

PTH2R = found not on osteoclasts on blasts

PTH/PTH1R signaling:

• decreases osteoclast V-ATPasae activity (slows down H+ ion secretion and bone breakdown)
• at the same time, it also increases RANKL secretion from osteoblasts which promotes osteoclast gene expression and upregulates # of osteoclasts

Question 7

How does magnesium levels inhibit PTH?

Answer 7

Severely chronic magnesium Deficency can inhibit PTH release from secretory vesicles

Question 8

What three forms of calcium are present at all times in the body

Answer 8

1) ionized calcium (50%)
- this is the physically active form

2) protein bound to albumin and calmodulin (40%)
- this is inactive

3) complexed to compounds to citrate/phosphate ions

Question 9

What are the effects of calcium entering cytoplasm?

Answer 9

Calcium moving to cytoplasm (low concentration) from organelles and ECF (high concentration) activates gPCR signaling, PIP hydrolysis, PKC activation and cellular effects

all lead to calcium replenishment to organelles and ECF

Question 10

Calcitonin effects

Answer 10

Reduces blood calcium levels and is secreted in response to hypercalcemia

Has two effects:

• suppresses renal tubular reabsorption of calcium
• inhibits bone resorption by minimizing flux of calcium from bone -> blood

overall has minimal influence on plasma calcium levels at any time

Question 11

What are other hormones that regulate bone calcium

Answer 11

Thyroid hormone
- stimulates bone resorption

Adrenal and gonadal steroids (especially estrogens and testosterone)

• stimulates osteoblasts and inhibit osteoclast (bone growth)
• also increases intestinal calcium absorption and decrease renal calcium and phosphate excretion

Leptin
- inhibits bone formation in unknown ways

Question 12

Estrogen effects on bone

Answer 12

Binds to ERa receptors on multiple aspects of bones

1) chondrocytes
- turns on nuclear-initiated signaling to initiate epiphyseal closure

2) periosteal cells
- unknown mechanism but attenuates apposition
- stimulation of periosteal apposition in (males only)

3) osteoprogenitors
- turns on non-nuclear-initiated signaling which attenuates endocortical bone reabsorption

4) osteoclasts
- initiates nuclear-initiated signaling which attenuates trabecular bone resorption

also with mechanical strain induces to unliganded ERa receptors on osteoprogenitors to stimulate periosteal apposition

Question 13

Androgens affects on bone

Answer 13

Binds to AR receptors on osteoblasts and osteocytes to stimulate trabecular bone formation

Question 14

Glucocorticoids (cortisol/aldosterone) affect on bones

Answer 14

Osteoblast effects

• decreases proliferation/differentiation
• increases apoptosis of osteoblasts
• decreases matrix formation up up regulating collagenase 3 enzymes and dose regulate ting collagen 1
• decreases osteocalcin

Osteoclasts effects

• increases cell recruitment
• increases differentiation to osteoclasts
• increases osteoclasts -> bone surface

Also indirectly enhances PTH responsiveness, without elevating levels of PTH

Question 15

Growth hormone effects on bone

Answer 15

GH effects on bone
1) binds via IGF-1 on chondrocytes which promotes endochondrial ossification (linear growth)

2) binds via IGF-1 on osteoclasts to promote bone resorption
3) binds GH directly on osteoblasts to stimulate more IGF-1 release which works osteoclasts

overall increases urinary excretion of calcium, decreases a urinalysis excretion of phosphate, increases linear growth and bone turnover

Question 16

Vitamin K functions on bone

Answer 16

Improves osteoblast functions and stimulates bone formation via increasing genesis of osteoblasts and increasing RANK and alkaline phosphatase activity

Inhibits bone resorption via inducing osteoclast apoptosis and decreasing RANKL and increasing OPG

also increases gamma-carboxylation which regulates bone mineralization

warfarin blocks vitamin K action which decreases all of these actions

Question 17

Osteoporosis and osteopenia information

Answer 17

A reduction of bone mineral density with an increased susceptibility to fractures

Rates of bone loss accelerate in women after loss of estrogen production (menopause)

Use DEXA scans to determine severity of bone density reduced

Question 18

Hyperparathyroidism clinical symptoms

Answer 18

Most patients either present asymptomatic or kidney stones

Other symptoms

• lethargy
• drowsiness
• inability to concentrate
• depression
• confusion
• proximal muscle weakness, hypotonia, decreased reflexes
• polyuria, polydipsia, dehydration
• nausea, vomiting, anorexia
• increased risk of peptic ulcers
• increased risk of pancreatitis
• broad T-waves in ECG
• corneal calcifications
• bone pain and fractures

Question 19

What is the most common cause of hypoparathyroidism?

Answer 19

Neck surgery

Question 20

Pseudohypoparathyrodism

Answer 20

Shows hypocalcemia, hyperphosphatemia with an INCREASED concentration of PTH

Confirmation of the diagnosis is made by demonstrating a lack of increase in plasma or urinary cAMP in response to PTH infusion

**classic form is due to end-organ resistance to PTH caused by a genetic defect resulting in an abnormal regulatory G protein subunit

Question 21

Renal osteodystrophy

Answer 21

CKD causes decreased ability to form active vitamin D as well as increased retention of PO43-
- this results in hyperphosphatemia and hypocalcemia

Will also cause a rise in PTH in blood, however the kidney cant respond well

Treatment = vitamin D w/ PO43- reduction therapy to prevent further bone loss and excessive hydroxyapatite crystal formation

Question 22

Paget disease of bone

Answer 22

Ares of accelerated bone turnover due to increased focal osteoclast activity which leaves with “punched-out” lesions on bones that are disorganized

is caused by increased sensitivity of osteoclasts to calcitriol and RANKL and increased plasma alkaline phosphatase

Shows elevated collagen and hydroxyproline in the urine and plasma

Treatment = bisphosphonates (present with anti-osteoclast activity)

Question 23

How do PTH and active vitamin D differ in effects on serum blood concentration?

Answer 23

PTH = increases calcium and decreases phosphate

1,25OH = increases both calcium and phosphate