BONE METABOLISM

NURINA TYAGITABIOCHEMISTRY DEPARTMENT

MEDICINE FACULTY OF UNISSULA

LEARNING OUTCOME• BONE OVERVIEW• MINERALISASI TULANG• ALKALI PHOSPHATASE• VITAMIN D• CALCIUM

BONE OVERVIEW BONE COMPOSITION REMODELLING CYCLE

BONE’S CELLS

BONE COMPOSITIONPENYUSUN:ORGANIK (KOMPONEN PROTEIN)90-95 % Kolagen tipe I5-10% Kolagen tipe V & protein non kolagen

INORGANIK (KOMPONEN MINERAL):Terutama adalah crystalline hydroxyapatite (Ca10(PO4)6(OH)2)Dan sodium, magnesium, karbonat, Fluoride99% kalsium tubuh berada di TULANGHidroksiapatit berguna untuk bone strength & resilience

TULANG merupakan struktur dinamis yang secara kontinyumengalami siklus REMODELLINGTujuan REMODELLING : tulang dapat beradaptasi thd perubahan(misal: kenaikan BB, pengaruh hormon)

Siklus REMODELLING ini t.d:RESORPSI penyerapan kembali mineral yg diperlukan tubuh

dilakukan oleh sel OSTEOKLASDEPOSISI penumpukan mineral dalam tulang

Dilakukan oleh sel OSTEOBLAS

REMODELLING CYCLE

OSTEOSIT

Berasal dari osteoblas Ditemukan di tulang

matur Terlibat dalam

pemeliharaan matrikstulang

Usianya sangat panjang,average half life: 25 years

BONE’S CELLS

RUFFLED BORDER: Berperandlm resorpsi tulang

Enzim ATPase mengeluarkan proton melintasi ruffled border arearesorpsi semakin me↓kan pH microenvironment (pH menjadi ≤4) ↑solubilitas hidroksiapatit Ca2+, H3PO4, H2CO3, & air demineralisasi

OSTEOKLAS

Lysosomal acid protease (mis. Katepsin) released cerna matriksprotein tulang transfer ke kapiler

OSTEOBLAST

Sel mononuklear berasal dariprekursor mesenkimal pluripoten

Fungsi:• Sintesis protein tulang • Sintesis berbagai Growth factor &sitokin2

• Bertanggung jawab deposisi matrikstulang baru (osteoid) &mineralisasinya

Osteoblast mengendalikan mineralisasi melalui pengaturanpassage ion kalsium & fosfat yang melintasi membranpermukaan osteoblast

MINERALISASI TULANG MINERALISASI PENGATURAN FUNGSI OSTEOBLAS

& OSTEOKLAS

1. Pembentukan kristal hidroksiapatit dalam vesikel matriks yangbertunas dari permukaan membran kondrosit, osteoblas, &odontoblast

2. Propagasi hidroksiapatit ke matriks ekstraselular & deposisidiantara fibril kolagen

3. Penghambatan pembentukan hidroksiapatit oleh pirofosfatinorganik ekstraselular

4. Tissue-nonspecific alkaline phosphatase (TNAP) hydrolisapirofosfat sediakan fosfat inorganik u/ mineralisasi

MINERALISASI

Regulation of osteoBlastsfunction

• Stimulation• PTH (fast reaction - activation of calcium pump ? – pumping Ca to

ECF)

• 1,25 Dihydrocholecalciferol

• IL-1

• T3, T4

• hGH, IGF-1 (insuline-like growth factor)

• PGE2 (prostaglandine)

• TNF (tumor necrosis factor)

• Estrogens ?

• Inhibition• Corticosteroids

Regulation of osteoClastsfunction

• Stimulation• PTH (not directly – through stimulation of osteoblasts)• 1,25 Dihydrocholecalciferol (not directly – through

stimulation of osteoblasts)• IL-6, IL-11

• Inhibition• Calcitonin (directly – receptors)• Estrogens (by inhibiting production of certain

cytokines)• TGF-β (transforming growth factor)• PGE2(prostaglandine)

Merupakan enzim glikoprotein yangterdapat di membran sel osteoblast,

termasuk Famili enzim zincmetalloprotein.

Fungsi: memisahkan gugus fosfatterminal dari ester fosfat organikBone alkaline phosphatase (BAP):

bone-specific isoform of alkalinephosphatase

BAP reflects the biosynthetic activityof these bone-forming cells.

BAP has been shown to be asensitive and reliable indicator of bone

metabolism.

ALKALI FOSFATASE

PENINGKATAN BAP :Jika Aktivitas osteoblastik ↑Misal:Paget diseaseOsteomalasia

BAP TUMOR MARKER Osteogenic sarcoma Metastasis tulang Leukemia Myelofibrosis Myeloma tumor marker Hyperthyroidism

Secara fisiologis ↑ : Pertumbuhan anak Orang dewasa > 50 tahun Bone growth Healing fracture Akromegali

MALES:<2 years: 25-221 mcg/L2-9 years: 27-148 mcg/L10-13 years: 35-169 mcg/L14-17 years: 13-111 mcg/LAdults: < or =20 mcg/L

FEMALES<2 years: 28-187 mcg/L2-9 years: 31-152 mcg/L10-13 years: 29-177 mcg/L14-17 years: 7-41 mcg/LAdultsPremenopausal: < or =14 mcg/LPostmenopausal: < or =22 mcg/L

NILAI NORMAL BAP

VITAMIN D VITAMIN D DALAM TUBUH VIT D DEFICIENCY VIT D TOXICITY

VITAMIN D• Vitamin D is not strictly a vitamin since it

can be synthesized in the skin• Only when sunlight is inadequate is a dietary

source required• The main function : regulation of calcium

absorption and homeostasis

17

18

hidroksilasi

calcidiol

calcitriol

Peran lain calcitriol: Sekresi insulin Sintesis & sekresi

parathyroid & thyroidhormon

Inhibisi produksi IL & Ig Diferensiasi monosit sel

prekursor Modulasi proliferasi sel

19

Vitamin D adl hormon steroid yang mengatur ekspresigen tertentu dan interaksinya dg reseptor intracellular

VIT D DEFICIENCY• Rickets :the bones of children are under mineralized as

a result of poor absorption of calcium• Osteomalacia (in adults ):results from demineralization of bone in

women who have little exposure to sunlight,often after several pregnancies

VIT D TOXICITY• contraction of blood vessels• high blood pressure• calcinosis—the calcification of soft tissues.

FOOD SOURCE :Fortified milk, liver, butter & fatty fish

RDI : 2,5 mg

CALCIUMo FUNGSIo CALCIUM TUBUHo HORMONAL REGULATORSo CALCIUM HOMEOSTASIS

CALCIUM• Mempunyai bermacam2

fungsi, a.l : Pembentukan tulang &

gigi Penjalaran impuls saraf Kontraksi otot Koagulasi darah Signalling intraseluler Sekresi enzim pencernaan Sekresi & kerja hormon

CALCIUMKation EKSTRASELULAR utama pada manusia.95-99% kadar Kalsium tubuh tersimpan di TULANG sebagai

KRISTAL HIDROKSIAPATIT Sisanya tersimpan di CAIRAN EKSTRASELULER dan

exchangeable dengan :• Periosteal fluid• Bone-forming surfaces• Soft tissuesKeseimbangannya tergantung bone FORMATION &RESORPTION (diatur oleh HORMON)

Konsentrasi Kalsium plasma: 8.8-10.3 mg/dL (2.20-2.58mmol/L)Dipelihara oleh: Parathyroid hormone (PTH) Metabolit vit D Kalsitonin Sitokin : TGF-β, IL-6

Target sites :

Absorbsi Reabsorbsi & ekskresi Akresi & mobilisasi

Kalsium tubuh dlm 3 bentuk:1.Non diffusible calcium bound to albumin (45%)2.Diffusible complexes of calsium w/ lactate, bicarbonate, fosfat,

sulfat, sitrat, anion lain (5%)3.Diffusible ionized calcium, Ca2+ (50%) physiological active

form diatur oleh klnj. PARATYROIDKeseimbangan ke-3 bentuk kalsium dipengaruhi oleh pH:pH 6.8 Ca2+ sebesar 54%pH 7.8 Ca2+ sebesar 38%

PHOSPHATE

80% bergabung dengan kalsium kristal HIDROKSIAPATIT diTULANG

Dietary requirements• Dietary requirements:

• Adult : 800 mg/day;• Women during pregnancy, lactation and post-

menopause: 1.5 g/day;• Children (1-18 yrs): 0.8-1.2 g/ day;• Infants: (< 1 year): 300-500 mg /day

• Food Sources:• Best sources: milk and milk product;• Good sources: beans, leafy vegetables, fish,

cabbage, egg yolk.

• Absorption of calcium:• in small intestine (duodenum), first half jejunum

against electrical and concentration gradient, by anenergy dependent active process, which influenced byseveral factors.

MechanismSimple diffusion

An active transport involving Ca pump(Ca2+-ATPase), requiring calcitriol

Uptake by the brush-bordercell membraneDiffusion through cytoplasm

Factor promoting Ca absorption1. Vit.D induce the synthesis of Ca binding protein inthe intestinal epithelial cells and promotes Caabsorption.

2. Parathyroid hormone (PTH) enhances Ca absorptionthrough the increased synthesis of calcitriol.

3. Acidity (low pH) is more favorable for Ca absorption.4. Lactose promotes calcium uptake by intestinal cell.5. Lysine and arginine facilitate Ca absorption.

Factor inhibiting Ca absorption1. Phytates and oxalates form insoluble salts andinterfere with Ca absorption.2. The high content of dietary phosphate results in theformation of insoluble Ca phosphate and prevent Cauptake.

Dietary ratio of Ca : P ---1:1 to 2:1--- is ideal for Caabsorption.

3. The free fatty acids are react with Ca to forminsoluble Ca soaps.4. The alkaline condition (high pH) is unfavorable forCa absorption.5. High content of dietary fiber interferes with Caabsorption.6. Low estrogen levels (postmenopausal women)

intakeexcretion

1000 gCa++stored inbone

Calcium homeostasis

BloodCa++

small intestine

kidney

Ca++lost in urine

Calcium inthe diet

calcium lost in feces

Ca++ absorbedinto blood

calcium resorption

calcium deposition

storagebone

Calcium cycling in bone tissue• Bone formation

• Osteoblasts• Synthesize a collagen matrix that holds

Calcium Phospate in crystallized form• Once surrounded by bone, become

osteocyte

• Bone resorption• Osteoclasts

• Change local pH, causing Ca++ andphosphate to dissolve from crystalsinto extracellular fluids

Hormonal Regulators• Calcitonin (CT)

• Lowers Ca++ in the blood• Inhibits osteoclasts

• Parathormone (PTH)• Increases Ca++ in the blood• Stimulates osteoclasts

• 1,25 Vitamin D3• Increases Ca++ in the blood• Increase Ca++ uptake from the gut• Stimulates osteoclasts

Calcitonin (CT)

• Secreted from the C cellsin the thyroid

• Lowers Ca++ in blood• Promotes deposition of

Ca++ into bone (inhibitsosteoclasts)

• Control of secretion fromc-cells:

CT

Parathormone (PTH)• Increases Ca++ in blood• Increases Ca++ resorption from the bone

• Stimulates osteoclasts• Increases number of osteoclasts

• Increases Ca++ resorption from nephron• Control of secretion:

• Necessary for fine control of Ca++ plasmalevels

1,25 Vitamin D3• Increases Ca++ uptake from the gut

• Increase transcription and translation of Ca++ transport proteins in gut epithelium

• Minor roll: also stimulates osteoclasts• Increase Ca++ resorption from the bone

Cholesterol precursor 7-dehydrocholesterol

UV

Vitamin D3

25 Vitamin D3

1,25 Vitamin D3

Low plasma Ca++ increase kidney enzymes

Calcium homeostasis

BloodCa++

small intestine

kidney

Ca++

Ca++

Ca++

bone 1,25 Vit. D3 (+)

1,25 Vit D3

deposition

Calcitonin (-)

Ca++PTH

Parathormone (+)

resorption

Regulation of Calcium Homeostasis

Defisiensi Calcium• Defisiensi vit D• Hipomagnesemia• Hipolbuminemia• Inadekuat diet• Alkalosis menurunkan serum Ca++ dengan

meningkatkan ikatan Ca dg serum albumin TETANI

Calcium Deficiencies -Rickets

weakness and deformity of the bones that occurs fromvitamin D deficiency or dietary deficiency of Ca and Pin a growing person or animal.

Calcium Deficiencies -Osteoporosis

progressive loss of bone density, thinning of bone tissueand increased vulnerability to fractures in the elderlypeople of both sexes.

Fosfor• ANION INTRASELULER terbanyak• FUNGSI :Counter ion Ca++ dalam mineralisasiTransferable functional group on

nucleotide triphosphateBuffer dalam darah

o DEPLESI : oleh karena ALKALOSIS

Functions of Phosphorus• Essential for the development of bones

and teeth• Phospholipids, Phosphoproteins• Component of:

• DNA & RNA• ATP, NAD+, NADP+

• Energy metabolism: ATP, GTP• Maintenance of blood pH: phosphate

buffer system

Dietary requirements• The recommended dietary allowance (RDA)

of phosphate is based on the intake ofcalcium.• For adult, the ratio of Ca:P of 1:1 is

recommended (800mg/day);• For infant, however, the ratio is around 2:1,

which is ratio found in human milk.• Sources:

• milk, cereals, leafy vegetable, meat, eggs.

Absorption and Excretion

Absorption:Phosphate absorption occur from jejunum1. Calcitriol promotes phosphate uptake along with calcium.2. absorption of P and Ca is optimum when the dietary Ca:P is

1:1-2:1.3. acidity favors while phytate decreases phosphate uptake by

intestinal cells.

Excretion:About 500 mg phosphate is excreted in urine per day. The

reabsorption of phosphate by renal tubules is inhibited by PTH.

• Importance of Ca:P ratio• The ratio of plasma Ca:P is important for calcification of

bones.• The product of Ca×P (in mg/dl) in child is around 50 and

in adults around 40. This product is less than 30 in rickets.

• Phosphorus Deficiency• Rickets, osteomalacia, osteoporosis

hormone

osteolysis

P excretion from kidney

osteogenesis

Ca excretion from kidney

Blood phosphorus

Blood calcium

1,25 DHCC

Ca absorption in intestine

PTH CT

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Factors Regulating Ca and P

F. Saraç & F. Saygılı (2007) Causes of High Bone AlkalinePhosphatase, Biotechnology & Biotechnological Equipment,21:2, 194-197, DOI:10.1080/13102818.2007.10817444

REFERENCES

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