dr. Susila Sastri M.BiomedBahagian Biokimia

FK-UNAND

• extracellular calcium (Ca2+ : 5 mmol/L and is very rigidly controlled.

• amounts of calcium: associated with intracellular organelles such as mitochondria and the endoplasmic reticulum, the intracellular concentration of free or ionized calcium (Ca2+ ) is very low: 0.05–10 mmol/L.

Struktur tulangBone : connective tissue, substantial

metabolic activity. type 1 collagen: the major protein (90%)calcium-rich crystals : hydroxyapatite

(Ca10[PO4]6[OH]2)Microarchitecture: reservoir of calciumOsteoid: noncalcified organic matrix

Cristal ApatiteComplexes of cationic Ca2+ matched

by HPO4 2–, CO32–, OH–, or F– as anions. carbonate apatite Ca10(PO4)6CO3hydroxyapatite Ca10(PO4)6 (OH)2fluoroapatite Ca10(PO4)6F2

In adults, more than 1 kg calcium is stored in bone.

Calcium circulationionized Ca2+: active form (50% of total calcium).

protein-bound: bound to negatively charged albumin (40%); Ca2+ buffers

Complexed : citrate and phosphate: (10%).

Fungsi Ca

• Bone component: 1–1.5 kg Ca2+ most of which (about 98%) is located in the mineral substance of bone

• Signaling substance: Ca2+ ions act as second messengers in signal transduction pathways: – exocytosis – muscle contraction – cofactors in blood coagulation

• Enzymes Co –factor • Proteins bind Ca2+ via oxygen ligands,

Factors influencIng calcium homeostasis

Parathyroid hormone (PTH)Vitamin D

25-hydroxycholecalciferol (25(OH)D3) is the main liver storage form of vitamin D

1,25(OH)2D3 increases serum concentrations of calcium and phosphate

Calcitonin inhibits osteoclastic bone resorption

Calcium effects• calcium sensors : biochemical effects

of Ca2+ in the cytoplasm (Ca2+ binding proteins) : annexins, calmodulin, and troponin C in muscle

• Calmodulin: Binding of four Ca2+ ions• Ca2+ ions : regulate the activity of

enzymes, ion pumps, and components of the cytoskeleton.

Bone remodeling • Mineralization : Deposition of Ca2+ in bone and Ca2+

mobilization from bone are regulated by at least 15 hormones and hormone like signaling substances.

• These mainly influence the maturation and activity of bone cells.

• Osteoblasts : deposit collagen, Ca2+ and phosphate, and thereby create new bone matter

• Osteoclasts : secrete H+ ions and collagenases that locally dissolve bone (bone remodeling).

• Osteoblasts and osteoclasts mutually activate each other by releasing cytokines and growth factors.

• bone formation and bone breakdown : balance.

Calcitonin• Calcitonin: A polypeptide hormone

(32-amino acid) residues that is synthesized in the parafollicular cells (C cells) of the thyroid gland.

• Calcitonin is secreted in response to elevated blood Ca2+ levels.

• IP3: Inositol 1,4,5-trisphosphate (inositol trisphosphate); a second messenger

• IP3 bind to receptors on the endoplasmic reticulum (ER) to cause the rapid efflux of Ca2+ from the ER into the cytoplasm.

Parathyroid hormone• PTH: 84-amino acid polypeptide

hormone that is synthesized in the parathyroid gland and is secreted in response to low blood Ca2+ levels.

• PTH: increase the Ca2+ concentration in the blood by stimulating osteoclast formation and activity, thus releasing bone calcium and phosphate into the blood

Vitamin D

• Vitamin D3: a secosteroid formed by the action of UV light on 7-dehydrocholesterol.

• The active form of vitamin D: hormone 1,25-dihydroxycholecalciferol (calcitriol), formed in the kidney in response to elevated PTH levels.

• It binds to nuclear receptors in intestine, bone, and kidney to activate the expression of calcium-binding proteins.

Maintaining bone mass - the bone remodeling cycle.

Resorption and formation of bone by osteoclasts and osteoblasts is coupled

• The Ca2+ selective hormones calcitriol, parathyroid hormone, and calcitonin influence this interaction in the bone cells.

• Parathyroid hormone promotes Ca2+ release by promoting the release of cytokines by osteoblasts.

• Cytokines: stimulate the development of mature osteoclasts from precursor cells

• Calcitonin inhibits this process. At the same time, it promotes the development of osteoblasts

• Osteoporosis: women following the menopause (reduction in estrogen levels)

• Estrogens normally: inhibit the stimulation of osteoclast differentiation by osteoblasts. If the effects of estrogen decline, the osteoclasts predominate and excess bone removal occurs.

Calcitriol• steroid hormone calcitriol in bone are

complex. – promotes bone formation by stimulating

osteoblast differentiation, important in small children, in whom calcitriol deficiency can lead to mineralization disturbances

– increases blood Ca2+ levels through increased Ca2+ mobilization from bone.

• An overdose of vitamin D (cholecalciferol), the precursor of calcitriol, can therefore have unfavorable effects on the skeleton similar to those of vitamin deficiency (hypervitaminosis)

Calcium homeostasis • Ca2+metabolism: balanced in healthy

adults. • 1 g Ca2+ : taken up per day, about 300 mg

of which is resorbed. • The same amount is also excreted again. • The amounts of Ca2+ released from bone and

deposited in it per day are much smaller. • Milk and milk products, especially cheese,

are particularly rich in calcium.

CLINICAL CORRELATION

• Malignancies or hyperparathyroidism : Hypercalcemia : kidney stones

• Osteoporotic : Estrogen decrease• Genetic conditions:

• familial hypocalciuric hypercalcemia • hyperparathyroidism.

• Osteomyelitis• osteosarcoma