Skeleton and Metabolism

Question 1

where are osteoclasts derived from?

Answer 1

haematopoietic stem cells

Question 2

where are osteoblasts derived from?

Answer 2

mesenchymal stromal stem cells

Question 3

where are osteocytes derived from?

Answer 3

osteoblasts

when osteoblasts become encased in the bone matrix they deposit, they become osteocytes

Question 4

describe the process of bone remodelling

Answer 4

a continuous process regulated and initiated by hormones, internal signals and environmental stressors such as micro-stresses and fractures

osteocytes as the master controllers for bone remodelling stimulate osteoclast differentiation

osteoclasts eat away at bone through carbonic acid secretion, digest protein matrix with enzymes - bone resorption

osteoblasts are activated from mesenchymal stromal cells to form new bone - lay down organic osteoid matrix

Question 5

different metabolic interactions of bone that affect plasma Ca conc

Answer 5

oestrogen, cortisol, PTH (parathyroid hormone), vitamin D, calcitonin

oestrogen is essential for bone health in all gender

high cortisol can lead to excess resorption - favoured over formation

PTH increases to increase serum Ca conc

vitamin D is converted to its active form calcitriol

Question 6

how PTH increases plasma Ca2+ concentration

Answer 6

promotes bone remodelling = increases Ca2+ and phosphate release from bone minerals

binds to receptors on osteoblasts and osteocytes which activate osteoclasts through signalling pathways. osteoclasts - bone resorbing, favoured under persistent, fast PTH doses.

increases calcium renal absorption, phosphate renal excretion, vitamin D conversion to increase calcitriol and Ca2+ gut absorption

Question 7

how does vitamin D help maintain - increase and decrease - plasma Ca2+ conc?

Answer 7

vitamin D from diet and sunlight is converted into its active form calcitriol through two enzymes

calcitriol increases Ca2+ gut absorption

inhibits PTH via negative feedback as increasing Ca2+ gut absorption = increases plasma Ca2+ = Ca2+ binds to PTH chief cell GCPR receptors and decreases PTH

Question 8

how do osteocytes communicate, and with what do they communicate with?

Answer 8

communicate with each other, surface cells and systemic circulation

osteocytes embedded in bone matrix live in lacunae with a canalicular network allowing communication

Question 9

what is FGF-23? effect of FGF-23 on phosphate homeostasis? what factors increase FGF-23, and what does it inhibit?

Answer 9

fibroblast growth factor 23 secreted by osteocytes. has a short half life as it’s cleaved and degraded quickly. acts on kidney receptors.

increases renal phosphate excretion by decreasing sodium-phosphate reabsorption from the PCT.

Question 10

what factors increase FGF-23? what does it inhibit?

Answer 10

STIMULATED BY increased high phosphate conc. = FGF-23 secreted to increase renal excretion.

FGF-23 secretion increased by calcitriol - increase in phosphate gut absorption = increased plasma phosphate conc = calcitriol acts at renal sites = FGF-23 is secreted

inhibits calcitriol synthesis

Question 11

what is osteoporosis?

Answer 11

loss of bone mass - the organic and mineral matrix

Question 12

what can cause osteoporosis?

Answer 12

endocrine causes - hypogonadism causing oestrogen deficiency, excess glucocorticoids, overactivity of the thyroid gland leading to hyperparathyroidism and hyperthyroidism

malignancy, drug-induced, renal disease, nutritional

age is the only non-pathological cause

Question 13

what is osteomalacia?

Answer 13

loss of bone mineralisation - also known as rickets in children

Question 14

what serum levels is osteomalacia characterised by?

Answer 14

low calcium, low phosphate, elevated alkaline phosphatase, elevated PTH

Question 15

what are the causes of osteomalacia and how do they contribute?

Answer 15

commonly vitamin D deficiency - it is needed in Ca2+ absorption of the gut. low levels can impair bone mineralisation.

rarely a vitamin D metabolism defect.

phosphate wasting due to excess FGF-23 for example, causing excess renal phosphate excretion

Question 16

what are the signs and symptoms of osteomalacia?

Answer 16

permanent bone growth deformities - they may be fully grown but with lesions and deformities associated with demineralisation

aches and pains

chronic fatigue

weak bones

Question 17

what is hypercalcaemia?

Answer 17

high calcium levels above the 2.2-2.6mmol serum range

Question 18

what are the clinical features of hypercalcaemia?

Answer 18

renal calcification like kidney stones, abdominal pain

bone pain due to PTH induced osteoporosis

cardiac arrythmias, even arrest in severe cases

Question 19

what are the possible causes of hypercalcaemia?

Answer 19

primary hyperparathyroidism in patients that have walked in

malignancy in hospital patients such as tumours secreting PTH - related peptide hormone, which activates PTH receptors

hyperthyroidism and excessive vitamin D intake are less common causes

Question 20

relationship between PTH and plasma Ca2+ conc?

Answer 20

decreased Ca2+ = increased PTH

PTH increases Ca2+ conc

proportionally great PTH increase with a small Ca2+ conc drop

Question 21

what is primary hyperparathyroidism?

Answer 21

benign adenoma in one of more of the parathyroid glands causing high Ca2+ levels

Question 22

two elements that compose bone - what are they? describe?

Answer 22

organic osteoid protein matrix - mainly type 1 collagen matrix secreted by bone cells. 25% of bone, provides flexibility and tensile strength,

bone mineral - hydroxyapatite (Ca and phos. compound). 75% of bone, gives rigid, compressive strength for weight-bearing.

Question 23

functions of bone (5)

Answer 23

support and movement

protection for internal organs

provides home for bone marrow - a source for blood cells and other stem cells

mineral reservoir for calcium and phosphate

acts as an endocrine gland = source of non-classical hormones

Question 24

define osteoclasts

Answer 24

haematopoietic stem cell derived cells - bone reabsorbing

remove old bone by dissolving the minerals and digesting the protein matrix

Question 25

define osteoblasts

Answer 25

mesenchymal stomal cell derived bone cells - bone forming

secrete organic osteoid matrix and participate in its mineralisation

Question 26

define osteocytes

Answer 26

osteoblast derived bone cells - mature bone cells

give rise to blood cells, maintain the balance between bone reabsorption and formation

Question 27

what is the plasma concentration range for calcium?

Answer 27

2.2-2.6 mmol

Question 28

how is daily calcium turnover maintained?

Answer 28

a balance between intake (diet) and output (renal excretion and faeces) is needed

fraction of renal resorption of Ca2+ can be adjusted to ensure balance

bone loss/resorption releases Ca2+ and phosphate into circulation

Question 29

describe the state of calcium in circulation

Answer 29

half of serum Ca2+ is free/ionised

the other half is protein (albumin) bound

Question 30

Q. Explain the role of vitamin D3 in calcium and phosphate metabolism

Answer 30

vitamin D from diet and sunlight – converted into its active forms by two enzymes, one in the liver (25-hydroxylase) and one in the kidney (1-a-hydroxylase)

calcitriol predominantly increases Ca2+ gut absorption, and also phosphate absorption
acts on kidneys = increases Ca2+ and phos. reabsorption

involved in negative feedback inhibition of PTH – increasing Ca2+ gut absorption = increases plasma [Ca2+] = decreases PTH, prevents excess Ca2+ loss

vitamin D deficiency seen in osteomalacia – loss of bone mineralisation

Question 31

Q. Explain how the gut, kidneys and skeleton are involved in maintaining the homeostasis of calcium and phosphate

Answer 31

gut:
involved in Ca2+ and phosphate gut absorption
- calcitriol (active vitamin D enhances Ca2+ gut absorption
- PTH secretions stimulate calcitriol synthesis when Ca2+ is low

kidneys:
- contains 1-a-hydroxylase, the second enzyme in converting vitamin D to its active form of calcitriol = increases Ca2+ gut absorption
- regulates Ca2+ and phosphate renal excretion and reabsorption
- FGF-23 acts on kidney receptors = increases phosphate renal excretion
- PTH increases Ca2+ renal reabsorption, increases phosphate excretion

skeleton:
- reservoir for Ca2+ and phosphate = released during osteoclast activity
- Ca2+ constantly deposited for bone formation and mineralisation
- PTH stimulates bone resorption through signalling pathways
- calcitonin released from thyroid gland opposes PTH = promotes Ca2+ deposition in bone