calcium homeostasis and bone

calcium ion physiological roles

• excitation-contraction coupling in the heart and other muscles

• secretion of hormones and other regulators by exocytosis

• synaptic transmission and other functions of the nervous system

• crucial role as intracellular second messenger (regulatory role in signaling pathways, membrane trafficking); regulates apoptosis, cell division, cell motility

• intracellular calcium levels are so tightly controlled, at levels ~10,000 fold lower than extracellular calcium concentration (large gradient), and rapidly fluctuate

• gradient across cell membrane: Maintained by ATP dependent calcium pumps (several types of Ca channels), Na-Ca exchangers, and calcium stores within intracellular compartments

levels of extracellular ionized calcium are..

tightly regulated within a narrow range (1.0-1.3 mM) to enable functioning of different physiological processes

are intracellular calcium levels tightly controlled

yes they are tightly controlled at levels 10,000 fold lower than extracellular calcium concentration and rapidly fluctuate

how much total calcium is physiologically active

only half of total calcium in serum/extracellular fluids are in physiologically active ionized Ca form, the rest is bound to albumin or complexed with anions (Phosphate, citrate)- this remaining fraction is metabolically inert/inactive, and not regulated by hormones

ionized Ca

• physiologically active form

• upregulated by parathyroid hormone and 1,25 dihydroxyvitamin D

• hormone calcitonin plays lesser (But opposing) regulatory role in terrestrial mammals

what is a challenge with calcium

• maintaining constant/narrow range of ionized Ca in extracellular fluid while compensating on hourly basis for changes in daily intake of calcium, bone metabolism, and renal fuction

• both parathyroid hormone and 1,25 dihydroxyvitamin D are very sensitive to small changes in Ca and both can regulate calcium exchange between extracellular fluid and gut, bone, and renal tubules

extracellular fluid calcium makes up how much of total body calcium

total calcium in extracellular fluid is only 1% of total body calcium, most calcium is sequestered in bone

bone homeostasis

• maintained by osteoblasts and osteoclasts within the basic multicellular unit, in a cycle of resportion and formation (coupled in part via osteoblasts regulating osteoclasts via cell-cell contact, paracrine signaling, and cell-bone matrix interaction)

• other systemic regulators on bone remodeling include growth hormone, glucocorticoids, thyroid hormones, sex steroids, growth factors, cytokines

osteoclasts

• large cells that move to surfaces of bone and secrete acid and enzyme to break down bone

• calcium resporption into bloodstream and also allows structural growth or repair

what are osteoclasts directly inhibited by

• directly inhibited by calcitonin (express calcitonin receptors)

• estradiol- inhibits osteoclast formation

what are osteoclasts indirectly regulated by

• indirectly regulated by parathyroid hormone and 1,25 dihydroxyvitamin D

• promote osteoclast formation

mononuclear cells

remove collagen remnants and prepares the bone surface for subsequent osteoblast mediated bone formation

osteoblasts

• bone forming cells that secretes bone matrix

• synthesize and deposit organic bone matrix proteins (collagens)

what is hydroxyapatite

deposited by osteoblasts, these are microcrystals and comprise 60% of bone, structure, and calcium/phosphate repository

what are osteoblasts directly regulated by

directly regulated by parathyroid hormone and 1,25 dihydroxyvitamin D (express receptors)

what are osteocytes

• derived from osteoblasts

• surrounded by osteoblasts secreted products

• in small chamber of fully formed calcified matrix of bone

what are mechanosensors

• in osteocytes

• coordinators of bone remodeling

• role in phosphate metabolism

bone remodeling

• bone remodeling is a continuous process of destruction & synthesis that allow bone to alter size, shape, & structure and maintains normal body calcium levels

• occurs throughout life (Most of adult skeleton replaced every 10 years)

• bones cant grow by cell division like other tissues (Mineralized structure)

osteoporosis

• disorder of the bones, honeycombed matrices become thinner, spaces between grow larger- bone is more porous & weaker, and easily fractured or broken

• gradual progression toward osteoporosis due to changes in the bone remodeling balance, leading to decreased mineralization and bone strength

• most common metabolic bone disease, most common in post menopausal women over 50 due to decrease in levels of estradiol & other sex steroids

• other endocrine causes may include hyperparathyroidism, hyperthyroidism or glucocorticoid excess

calcitonin

peptide hormone produced by parafollicular C cells of thyroid (0.1% of thyroid glands)

main function of calcitonin

inhibit osteoclast mediated bone resorption, keeps calcium in the bone

what is calcitonin secreted in response to

elevated levels of extracellular calcium concentration

calcium sensing receptor

GPCR, couples to various G proteins, Gaq, activates phospholipase C and induces intracellular calcium mobilization in response to extracellular calcium

does calcitonin play an essential physiological role in terrestrial mammals

• NO, removal of thyroid gland doesn’t have much effect on calcium handling or bone metabolism

• plays more important role in saltwater fish (Because its a challenge to maintain calcium homeostasis in ambient very high calcium concentration of sea water)

parathyroid hormone

peptide hormone secreted by four parathyroid glands adjacent to thyroid gland

overall function of parathyroid hormone

• raise ionized calcium levels in blood under tight control of extracellular calcium concentration

• want there to be secretion of parathyroid hormone when there is low external calcium

when is parathryoid hormone inhibited

inhibited secretion in response to elevated extracellular calcium levels

calcium sensing receptor parathyroid hormone

• same calcium sensing receptor as parafollicular C cells/calcitonin

• high extracellular calcium inhibits secretion of preformed parathyroid hormone in storage granules

• GPCR couples to various G proteins, Gaq activates phospholipase C and induces intracellular calcium mobilization and Gai which suppresses cAMP synthesis and cAMP linked PTH secretion

what is parathyroid hormone gene transcription inhibited by

high 1,25 dihydroxyvitamin D

what does hypocalcaemia (Low calcium) do to PTH gene transcription

increase mRNA stability via increased binding of protective proteins to 3’-UTR region of preproparathyroidhormone mRNA

parathyroid hormone effects bone

sustained elevated parathyroid hormone indirectly promotes osteoclast formation & activity by binding to parathyroid hormone receptors on osteoblasts & osteocytes (Causing these cells to regulate osteoclasts via signaling)

parathyroid effects intestine

calcium absorption effects are indirect, resulting from stimulating increased production of intestinally active vitamin D metabolite 1,25 dihydroxyvitamin D in the kidneys

kidney parathyroid hormone effects

• directly promotes tubular reabsorption of calcium

• calcium actively transported against gradient, predominantly in distal convoluted tubule

• also inhibits reabsorption of phosphate and bicarbonate

parathyroid hormone effects overall

increases inflow of calcium into extracellular fluid from bone, intestine, and kidney, defening body against hypocalcaemia (Low calcium)

Vitamin D

• Vitamin D (D2 and D3) different side chains & metabolic steps but similar final forms and biological activity, can be formed in the epidermis by photolysis (UV) of naturally occuring sterol precursors (cholesterol precursors)

• considered a prohormone than a vitamin

to be biologically active vitamin D must be

• metabolized further by liver

• liver metabolizes vitamin D to its prinicipal circulating form 25(OH)D

most important active metabolite form

• 1,25 dihydroxyvitamin D

• kidney and other tissues metabolize 25(OH)D to other metabolist and the most important active form 1,25 dihydroxyvitamin D

7-dehydrocholesterol

• there is cleavage turns into pre-vitamin D3

cholecalciferol/calciol

primarily bound to vitamin D binding protein (DBP), an alpha globulin produced in the liver

cholecalciferol/calciol gets converted to

• 25(OH)D/ calcidiol

• synthesized in the liver, but the major blood form of vitamin D

• can store in liver and adipose tissue until needed, then main control point at kidney

• that gets further converted to 1,25(OH)2 D/Calcitriol or 24,25-Dihydroxyvitamin D

if there is low calcium

• you get activation of enzyme 1a-hydroxylase and that will convert 25(OH)D/calcidiol (Main circulating form) into its active form of 1,25(OH)2D/Calcitriol

if there is high calcium

gets converted into its inactive form: 24,25-Dihydroxyvitamin D

nuclear vitamin D receptor (VDR)

• typicall form heterodimers with RXRs

• binding of VDR-RXR complex to VDRE attracts coactivators (May acetylate histones, or bridge gap to the initation complex)

• not all actions genomic (VDRs on membrane & other membrane bound proteins may mediate rapid effects on calcium influx & PKC activity)

• VDRs in bone, kidney, intestine, but also many other cell types like immune cells, testis, antiproliferative role in breast cancer

• most calcium increased effects via stimulation of Ca absorption/resorption in gut/kidney

1,25(OH)2D/Calcitriol bone

• increases osteoclast formation

• stimulates mineralization of osteoblasts

• maintain calcium balance through regulation of bone mineralization

1,25(OH)2D/Calcitriol Kidneys

• regulates kidneys metabolism to active vs inactive vitamin D forms

• increases calcitriol formation and decreases calcium excretion

• increase mRNA of calcium binding proteins that facilitate intracellular Ca movement, allowing efficient reabsorption of calcium from the urine

1,25(OH)2D/Calcitriol in intestine

• increase mRNA levels of calcium channels for uptake of Ca from lumen

• also increases vitamin D receptor mRNA

• increases phosphate absorption and renal resportion of phasphate

1,25(OH)2D/Calcitriol parathyroid hormone

• increases PTH secretion when calcium and phosphate levels are low

• but high levels of 1,25(OH)2D inhibit PTH gene transcription (therefore, indirectly keeps calcium & phosphate in bone)

most calcium increasing effects of 1,25(OH)2D/Calcitriol

via stimulation of Ca absorption/resorption in gut/kidney

rickets

• most often from exteme vitamin D deficiency in children (or due to a rare genetic cause)

• leads to decreased Ca and phosphate absorption from food, results in secondary hyperparathyroidism (PTH too high) and increased bone resorption (Weak or soft bones)

• skeletal deformities, delayed growth, pain
  

osteomalacia

• often refers to milder version in adults (Bone is already fused): mineralization of newly formed bone matrix is defective; due to lack of vitamin D, low Ca or low phosphate

• pain, muscle weakness

• may be associated with osteoporosis

fibroblast growth factor 23

• secreted by osteocytes and osteoblasts- bone

• role maintaining phosphate homeostasis

fibroblast growth factor 23 main effect in kidney

• main effects are in kidney

• inhibits expression of sodium/phosphate cotransporters, reducing renal phosphate reabsorption

• negative feedback of 1,25(OH)2D: inhibits 1a-hydroxylase, the key enzyme in the kidney that converts 25(OH)D into the active form of vitamin D (1,25(OH)2D increases phosphate absorption & reabsorption)

• inhibits PTH synthesis & secretion