Rate of GrowthRate of Growth

Varies at different age:Varies at different age:• maximal growth rate: fetusmaximal growth rate: fetus• highest postnatal growth: just after birthhighest postnatal growth: just after birth• slower rate in mid-childhoodslower rate in mid-childhood• increased growth rate during puberty / pubertal growth spurtincreased growth rate during puberty / pubertal growth spurt

girls 8-13 girls 8-13 boys 9-14 yearsboys 9-14 yearsdependent especially on GH and gonadal steroidsdependent especially on GH and gonadal steroids

• after puberty, the epiphyses of long bones fuse --> growth after puberty, the epiphyses of long bones fuse --> growth ceases --> maximal height achievedceases --> maximal height achieved

Growth and DevelopmentGrowth and Development� Is genetically determinedIs genetically determined� Its full potential depends on:Its full potential depends on:

• NutritionNutrition

• Health (illness and stress inhibit growth)Health (illness and stress inhibit growth)

• Hormones Hormones Growth Hormone (GH)Growth Hormone (GH) Somatomedins / Insulin-like Growth Factors: Somatomedins / Insulin-like Growth Factors:

IGF-I, IGF-IIIGF-I, IGF-II Thyroid hormones: Thyroid hormones:

Tri-iodothyronine (T3)Tri-iodothyronine (T3)Tetra-iodothyronine (T4) / ThyroxineTetra-iodothyronine (T4) / Thyroxine

Gonadal Steroids (sex hormones)Gonadal Steroids (sex hormones) ParathormoneParathormone 1,25-dihydrocholecalciferol (1,25 DHC / calcitriol)1,25-dihydrocholecalciferol (1,25 DHC / calcitriol) CalcitoninCalcitonin

BoneBone

Fungsi utama tulang

1. Fungsi ekstrimitas dan pelindung alat vital

2. Tempat melekat otot rangka

3. Menjadi tempat ion penting bagi tubuh seperti Ca,P,Mg,S yang sangat penting untuk kehidupan dan dapat digunakan tubuh saat tdk ada/kurang ion pd tubuh

4. Rumah bagi elemen hematopoetik

BoneBone Compact boneCompact bone

• Outer layer of bone, surrounding trabecular bone & bone marrow cavityOuter layer of bone, surrounding trabecular bone & bone marrow cavity

• Much denser, less active metabolicallyMuch denser, less active metabolically

• Compose 75% of bone in the bodyCompose 75% of bone in the body

• Nutrients are provided via Nutrients are provided via Haversian canalsHaversian canals blood vessels blood vessels

• Collagen arrangement around Haversian canals Collagen arrangement around Haversian canals osteon cylinders osteon cylinders (Haversian system)(Haversian system)

Trabecular boneTrabecular bone

• Spongy bone: bone spicules separated by spacesSpongy bone: bone spicules separated by spaces

• Compose 25% of bone in the bodyCompose 25% of bone in the body

• Nutrients diffuse from bone ECFNutrients diffuse from bone ECF

BoneBoneBoneBone Organic matrixOrganic matrix

• 30% content of compact bone30% content of compact bone

• Collagen fibers: 90-95%Collagen fibers: 90-95%Fibers extend primarily along the lines of tensional force; give the Fibers extend primarily along the lines of tensional force; give the

powerful tensile strengthpowerful tensile strength

• Homogeneous gelatinous medium – ground substance: 5-10%Homogeneous gelatinous medium – ground substance: 5-10%Extracellular fluids + proteoglycans (chondroitin sulfate & hyaluronic Extracellular fluids + proteoglycans (chondroitin sulfate & hyaluronic

acid)acid)Help control the deposition of calcium saltsHelp control the deposition of calcium salts

Bone saltsBone salts

• 70% content of compact bone70% content of compact bone

• Crystalline salts (principally calcium & phosphate): hydroxyapatite, Ca/P Crystalline salts (principally calcium & phosphate): hydroxyapatite, Ca/P ratio: 1.3-2.0; long, flat shaped crystal plates; compressional strength ratio: 1.3-2.0; long, flat shaped crystal plates; compressional strength

• Mg, Na, K, carbonateMg, Na, K, carbonate

Bone cellsBone cells

• OsteoblastsOsteoblasts

• OsteocytesOsteocytes

• OsteoclastsOsteoclasts

Bone cellsBone cells OsteoblastsOsteoblasts

Bone forming cellsBone forming cells Derived from bone marrow cell precursors Derived from bone marrow cell precursors Secrete large quantities of type I collagen + other matrix proteinsSecrete large quantities of type I collagen + other matrix proteins Secrete growth factors IGF-1, secrete cytokines IL-1, IL-6 Secrete growth factors IGF-1, secrete cytokines IL-1, IL-6 Receptors for PTH, DHC, estrogensReceptors for PTH, DHC, estrogens Differentiate into osteocytesDifferentiate into osteocytes

OsteocytesOsteocytes Rounded cells surrounded by bone matrixRounded cells surrounded by bone matrix Send long processes: Send long processes:

into the canaliculi, contact and form ‘tight junctions’ with into the canaliculi, contact and form ‘tight junctions’ with processes of other osteocytes, ramify throughout the bone processes of other osteocytes, ramify throughout the bone

function in Ca++ exchange with the ECFfunction in Ca++ exchange with the ECF

Figure 21–2.

Structure of compact and trabecular bone. The compact bone is shown in horizontal section (top) and vertical section (left). (Reproduced, with permission, from Williams PL et al (editors): Gray's Anatomy, 37th edition, Churchill Livingstone, 1989.)

Bone cellsBone cells

OsteoclastsOsteoclasts

Derived from hematopoietic stem cells through monocytesDerived from hematopoietic stem cells through monocytes

Erode and resorb previously formed bone:Erode and resorb previously formed bone: proton pump proton pump acidify the matrix ( acidify the matrix ( pH 4) pH 4) dissolves dissolves

hiydroxyapatite hiydroxyapatite calcium and phosphate ion calcium and phosphate ion acid proteases dissolve collagen acid proteases dissolve collagen amino acids amino acids shallow depression in the bone – bone-resorbing compartmentshallow depression in the bone – bone-resorbing compartment

OSTEOBLASTOGENESIS - OSTEOCLASTOGENESISOSTEOBLASTOGENESIS - OSTEOCLASTOGENESIS

Bone Marrow CultureBone Marrow Culture

Fibroblast Colony- Granulocyte-Macrophag Fibroblast Colony- Granulocyte-Macrophag Forming Unit Colony Forming UnitForming Unit Colony Forming Unit

(Osteoprogenitor cells) (Hematopoetic cells)(Osteoprogenitor cells) (Hematopoetic cells)Osteoblast, Fibroblast Osteoclast, MonocytesOsteoblast, Fibroblast Osteoclast, MonocytesChondrocytes, Adipocytes Macrophage ProgenitorsChondrocytes, Adipocytes Macrophage Progenitors ProgenitorsProgenitors PTHPTH CalcitriolCalcitriol RANK-LRANK-L

(-) (-)Osteoblastic Early pre-osteoclastOsteoblastic Early pre-osteoclast

precursor cellsprecursor cells (+)(+)

Late pre-osteoclastLate pre-osteoclast EstrogenEstrogen

(+)(+) (+)(+) AndrogenAndrogen (+)(+) OsteoblastOsteoblast OsteoclastOsteoclast

IGF-1IGF-1 Bone ResorptionBone Resorption Bone FormingBone Forming (RANK: receptor activator of nuclear factor kappa B) = (RANK: receptor activator of nuclear factor kappa B) =

(ODF: osteoclast differentiation factor)(ODF: osteoclast differentiation factor)

Osteoblast – Osteoclast CommunicationOsteoblast – Osteoclast CommunicationOsteoblast – Osteoclast CommunicationOsteoblast – Osteoclast Communication

osteoblast (& osteoblast precursors)osteoblast (& osteoblast precursors)

estrogens estrogens + + -- glucocorticoidsglucocorticoids + + - - estrogensestrogens

PTHPTH

osteoprotegerin (OPG) OPG-ligandosteoprotegerin (OPG) OPG-ligand

free-floating decoy receptorfree-floating decoy receptor (RANK ligand) (RANK ligand)

osteoclast precursors osteoclastosteoclast precursors osteoclast + +

RANK receptorRANK receptor RANK receptorRANK receptor

+ +

osteoclast activityosteoclast activity

RANK ligand RANK ligand bone resorptionbone resorption

(osteoblast) (osteoblast) ++

PTH, DHC (vit DPTH, DHC (vit D33), IL 1- 4 - 6-11-17, TNF-), IL 1- 4 - 6-11-17, TNF-alfaalfa

osteoblast (& osteoblast precursors)osteoblast (& osteoblast precursors)

estrogens estrogens + + -- glucocorticoidsglucocorticoids + + - - estrogensestrogens

PTHPTH

osteoprotegerin (OPG) OPG-ligandosteoprotegerin (OPG) OPG-ligand

free-floating decoy receptorfree-floating decoy receptor (RANK ligand) (RANK ligand)

osteoclast precursors osteoclastosteoclast precursors osteoclast + +

RANK receptorRANK receptor RANK receptorRANK receptor

+ +

osteoclast activityosteoclast activity

RANK ligand RANK ligand bone resorptionbone resorption

(osteoblast) (osteoblast) ++

PTH, DHC (vit DPTH, DHC (vit D33), IL 1- 4 - 6-11-17, TNF-), IL 1- 4 - 6-11-17, TNF-alfaalfa

OsteoblastOsteoblast

• Produces bone matrixProduces bone matrix

• Mediating osteoclast activityMediating osteoclast activity

parathormone (PTH)parathormone (PTH)

osteobalstic + osteobalstic + osteoprotegerin (OPG) ligandosteoprotegerin (OPG) ligand

precursorprecursor osteoblast osteoblast bone formation bone formation

cells +cells + + + soluble mediatorssoluble mediators

++

osteoclast bone resorption activityosteoclast bone resorption activity

release matrix growth factors release matrix growth factors

(transforming growth factor-(transforming growth factor-ββ / TGF- / TGF- ββ))

Bone Formation & ResorptionBone Formation & Resorption

Bone is constantly being resorbed and formedBone is constantly being resorbed and formed

ModellingModelling

Processes involved in formation of the skeletonProcesses involved in formation of the skeleton

Most active during childhood and adolescenceMost active during childhood and adolescence

Ceases at maturity (age 18-20 yrs)Ceases at maturity (age 18-20 yrs)

Long bones increase in diameter, change shape and develop a marrow Long bones increase in diameter, change shape and develop a marrow cavity cavity related to stresses and strains imposed on skeleton by gravity and related to stresses and strains imposed on skeleton by gravity and other factorsother factors

Bone strength adjustment to heavy loads /mechanical forces Bone strength adjustment to heavy loads /mechanical forces changes changes in bone shapes and thickness in bone shapes and thickness bone rearrangement for proper support bone rearrangement for proper support

Bone is constantly being resorbed and formedBone is constantly being resorbed and formed

ModellingModelling

Processes involved in formation of the skeletonProcesses involved in formation of the skeleton

Most active during childhood and adolescenceMost active during childhood and adolescence

Ceases at maturity (age 18-20 yrs)Ceases at maturity (age 18-20 yrs)

Long bones increase in diameter, change shape and develop a marrow Long bones increase in diameter, change shape and develop a marrow cavity cavity related to stresses and strains imposed on skeleton by gravity and related to stresses and strains imposed on skeleton by gravity and other factorsother factors

Bone strength adjustment to heavy loads /mechanical forces Bone strength adjustment to heavy loads /mechanical forces changes changes in bone shapes and thickness in bone shapes and thickness bone rearrangement for proper support bone rearrangement for proper support

Bone Formation & ResorptionBone Formation & Resorption

Bone is constantly being resorbed and formedBone is constantly being resorbed and formed

Remodelling Remodelling

Processes occurring at bone surfaces before and after adult Processes occurring at bone surfaces before and after adult development to maintain the structural integrity of the bone that development to maintain the structural integrity of the bone that continues throughout adult life continues throughout adult life

No net gain or loss of skeletal mass after longitudinal growth has No net gain or loss of skeletal mass after longitudinal growth has ceased. Bone resorption equally balanced by bone formation in a ceased. Bone resorption equally balanced by bone formation in a healthy skeleton healthy skeleton

Local process: bone-remodeling units Local process: bone-remodeling units osteoclasts resorb bone, osteoclasts resorb bone, osteoblasts form new boneosteoblasts form new bone

100 day cycle (3-4 months; 3 weeks resorption by osteoclasts, 100 day cycle (3-4 months; 3 weeks resorption by osteoclasts, deposition afterwards by osteoblasts)deposition afterwards by osteoblasts)

5% of bone mass is remodeled at any one time by 5% of bone mass is remodeled at any one time by ++ 2 million bone- 2 million bone-remodeling units; 4%/year for compact bone, 20%/year for trabecular remodeling units; 4%/year for compact bone, 20%/year for trabecular bonebone

Bone is constantly being resorbed and formedBone is constantly being resorbed and formed

Remodelling Remodelling

Processes occurring at bone surfaces before and after adult Processes occurring at bone surfaces before and after adult development to maintain the structural integrity of the bone that development to maintain the structural integrity of the bone that continues throughout adult life continues throughout adult life

No net gain or loss of skeletal mass after longitudinal growth has No net gain or loss of skeletal mass after longitudinal growth has ceased. Bone resorption equally balanced by bone formation in a ceased. Bone resorption equally balanced by bone formation in a healthy skeleton healthy skeleton

Local process: bone-remodeling units Local process: bone-remodeling units osteoclasts resorb bone, osteoclasts resorb bone, osteoblasts form new boneosteoblasts form new bone

100 day cycle (3-4 months; 3 weeks resorption by osteoclasts, 100 day cycle (3-4 months; 3 weeks resorption by osteoclasts, deposition afterwards by osteoblasts)deposition afterwards by osteoblasts)

5% of bone mass is remodeled at any one time by 5% of bone mass is remodeled at any one time by ++ 2 million bone- 2 million bone-remodeling units; 4%/year for compact bone, 20%/year for trabecular remodeling units; 4%/year for compact bone, 20%/year for trabecular bonebone

Bone Formation & ResorptionBone Formation & Resorption

Equilibrium Between Bone Deposition and AbsorptionEquilibrium Between Bone Deposition and Absorption

• In growing bones, the rate of bone deposition exceeds that of bone In growing bones, the rate of bone deposition exceeds that of bone absorptionabsorption

• The epiphyses of long bones fuse The epiphyses of long bones fuse growth ceases growth ceases maximal maximal height achieved (20-21 yrs) height achieved (20-21 yrs) peak bone mass age (35 yrs): peak bone mass age (35 yrs): the rate the rate of bone deposition and bone absorption are equal / constant total of bone deposition and bone absorption are equal / constant total bone mass / plateaubone mass / plateau

• AfterAfter 35 yrs: the rate of bone absorption exceeds that of bone 35 yrs: the rate of bone absorption exceeds that of bone deposition deposition osteopenia osteopenia osteoporosis osteoporosis

Bone Formation & ResorptionBone Formation & Resorption

Repair of a fractureRepair of a fracture

Maximal activation of all periosteal and intraosseous osteoblasts at Maximal activation of all periosteal and intraosseous osteoblasts at the fracture sitethe fracture site

Immediate formation of immense number of osteoblasts Immediate formation of immense number of osteoblasts development of large bulge of new organic matrix followed by development of large bulge of new organic matrix followed by calcium salts deposition calcium salts deposition callus formation; then reshaped into callus formation; then reshaped into appropriate structure within monthsappropriate structure within months

Bone GrowthBone Growth

During growthDuring growth

Epiphyseal plate Epiphyseal plate

• Plate of actively proliferating cartilagePlate of actively proliferating cartilage

• Separates epiphyses of long bones from its shaftSeparates epiphyses of long bones from its shaft

• Lays down new bone on the end of the shaft, Lays down new bone on the end of the shaft, finely balanced cycle of finely balanced cycle of cartilage growth, matrix formation and calcification of cartilagecartilage growth, matrix formation and calcification of cartilage

• Its width is proportionate to the rate of growth, affected by hormones, Its width is proportionate to the rate of growth, affected by hormones, most markedly by GH and IGF-1most markedly by GH and IGF-1

• Linear bone growth ceases after the epiphyses unite with the shaft of Linear bone growth ceases after the epiphyses unite with the shaft of the bone the bone (epiphysial closure)(epiphysial closure)::

>> Cartilage cells stop proliferating, hypertrophic Cartilage cells stop proliferating, hypertrophic vascularization, ossification. vascularization, ossification.

>> Epiphysial closure of bones is an orderly temporal Epiphysial closure of bones is an orderly temporal sequence sequence “bone age” can be determined by x ray “bone age” can be determined by x ray

Structure of a typical long bone before (left) and after (right) epiphysial closure

Bone GrowthBone Growth

Fetal developmentFetal development

Enchondral bone formationEnchondral bone formation

Most of the bonesMost of the bones

Modeled in cartilage Modeled in cartilage transformed into bone / ossificationtransformed into bone / ossification

Intramembranous bone formationIntramembranous bone formation

Clavicles, mandibles, bones of the skullClavicles, mandibles, bones of the skull

Mesenchymal cells form bonesMesenchymal cells form bones

The Hormones

Control of Growth Hormone SecretionControl of Growth Hormone Secretion

Brain stress centers Brain sleep centers chemical stimuliBrain stress centers Brain sleep centers chemical stimuli

sex steroidssex steroids

HypothalamusHypothalamus

GIH GRHGIH GRH

(Somatostatin) (Somatostatin)

Somatotroph cells of anterior pituitarySomatotroph cells of anterior pituitary

GHGH

Liver (and other organs)Liver (and other organs)

Somatomedins (IGF-I, IGF-II)Somatomedins (IGF-I, IGF-II)

TissuesTissues

Growth and cellular differentiation in bone, muscle and adipose tissueGrowth and cellular differentiation in bone, muscle and adipose tissue

activatesactivates inhibitsinhibits

Brain stress centers Brain sleep centers chemical stimuliBrain stress centers Brain sleep centers chemical stimuli

sex steroidssex steroids

HypothalamusHypothalamus

GIH GRHGIH GRH

(Somatostatin) (Somatostatin)

Somatotroph cells of anterior pituitarySomatotroph cells of anterior pituitary

GHGH

Liver (and other organs)Liver (and other organs)

Somatomedins (IGF-I, IGF-II)Somatomedins (IGF-I, IGF-II)

TissuesTissues

Growth and cellular differentiation in bone, muscle and adipose tissueGrowth and cellular differentiation in bone, muscle and adipose tissue

activatesactivates inhibitsinhibits

Growth Hormone and IGF-I ActionsGrowth Hormone and IGF-I ActionsGrowth Hormone and IGF-I ActionsGrowth Hormone and IGF-I Actions

Growth hormoneGrowth hormone

Na+ decreased lipolysis protein epiphysial Na+ decreased lipolysis protein epiphysial

retention insulin retention insulin synthesis growth synthesis growth

sensitivitysensitivity

IGF-IIGF-I

insulin-likeinsulin-like antilipolyticantilipolytic protein protein epiphysialepiphysial

activityactivity activity activity synthesis synthesis growth growth

Growth hormoneGrowth hormone

Na+ decreased lipolysis protein epiphysial Na+ decreased lipolysis protein epiphysial

retention insulin retention insulin synthesis growth synthesis growth

sensitivitysensitivity

IGF-IIGF-I

insulin-likeinsulin-like antilipolyticantilipolytic protein protein epiphysialepiphysial

activityactivity activity activity synthesis synthesis growth growth

Growth Promoting Actions of GH on Soft TissuesGrowth Promoting Actions of GH on Soft TissuesMediated by SomatomedinsMediated by Somatomedins

Growth Promoting Actions of GH on Soft TissuesGrowth Promoting Actions of GH on Soft TissuesMediated by SomatomedinsMediated by Somatomedins

• Increasing the number of cells (hyperplasia)Increasing the number of cells (hyperplasia) Stimulating cell divisionStimulating cell division Preventing apoptosis (programmed cell death)Preventing apoptosis (programmed cell death)

• Increasing the size of cells (hypertrophy)Increasing the size of cells (hypertrophy) Favoring protein synthesis (main structural Favoring protein synthesis (main structural

component of cell)component of cell)

•Stimulates aspects of protein synthesisStimulates aspects of protein synthesis Promotes amino acids uptake by cellsPromotes amino acids uptake by cells Promotes DNA transcriptionPromotes DNA transcription Promotes RNA translationPromotes RNA translation

• Inhibits protein degradationInhibits protein degradation

• Increasing the number of cells (hyperplasia)Increasing the number of cells (hyperplasia) Stimulating cell divisionStimulating cell division Preventing apoptosis (programmed cell death)Preventing apoptosis (programmed cell death)

• Increasing the size of cells (hypertrophy)Increasing the size of cells (hypertrophy) Favoring protein synthesis (main structural Favoring protein synthesis (main structural

component of cell)component of cell)

•Stimulates aspects of protein synthesisStimulates aspects of protein synthesis Promotes amino acids uptake by cellsPromotes amino acids uptake by cells Promotes DNA transcriptionPromotes DNA transcription Promotes RNA translationPromotes RNA translation

• Inhibits protein degradationInhibits protein degradation

SomatomedinsSomatomedins

Insulin-like growth factor-1 (IGF-I) and Insulin-like Insulin-like growth factor-1 (IGF-I) and Insulin-like growth factor-2 (IGF-II)growth factor-2 (IGF-II)

Polypeptide growth factors, interacts with GHPolypeptide growth factors, interacts with GH

Synthesized in and secreted by the liver, Synthesized in and secreted by the liver, osteoblasts osteoblasts && cartilage cartilage (chondrocytes)(chondrocytes) and other tissues in and other tissues in response to GH stimulationresponse to GH stimulation

In human bone matrix IGF-II is present in 10-15-fold In human bone matrix IGF-II is present in 10-15-fold greater concentrations than IGF-I greater concentrations than IGF-I

Stimulate osteoblast and chondrocyte proliferation, Stimulate osteoblast and chondrocyte proliferation, induce differentiation in osteoblasts and maintain the induce differentiation in osteoblasts and maintain the chondrocyte phenotype chondrocyte phenotype

Insulin-like growth factor-1 (IGF-I) and Insulin-like Insulin-like growth factor-1 (IGF-I) and Insulin-like growth factor-2 (IGF-II)growth factor-2 (IGF-II)

Polypeptide growth factors, interacts with GHPolypeptide growth factors, interacts with GH

Synthesized in and secreted by the liver, Synthesized in and secreted by the liver, osteoblasts osteoblasts && cartilage cartilage (chondrocytes)(chondrocytes) and other tissues in and other tissues in response to GH stimulationresponse to GH stimulation

In human bone matrix IGF-II is present in 10-15-fold In human bone matrix IGF-II is present in 10-15-fold greater concentrations than IGF-I greater concentrations than IGF-I

Stimulate osteoblast and chondrocyte proliferation, Stimulate osteoblast and chondrocyte proliferation, induce differentiation in osteoblasts and maintain the induce differentiation in osteoblasts and maintain the chondrocyte phenotype chondrocyte phenotype

SomatomedinsSomatomedins

• Promotes skeletal and extra skeletal growthPromotes skeletal and extra skeletal growth

• Insulin-like effectsInsulin-like effects

Increased glucose uptakeIncreased glucose uptake

Increased amino acids uptakeIncreased amino acids uptake

Increased protein synthesisIncreased protein synthesis

• Glucocorticoids reduce IGF activityGlucocorticoids reduce IGF activity

• High levels of estrogens inhibits IGF productionHigh levels of estrogens inhibits IGF production

Effects of Thyroid Hormones on Growth and DevelopmentEffects of Thyroid Hormones on Growth and DevelopmentEffects of Thyroid Hormones on Growth and DevelopmentEffects of Thyroid Hormones on Growth and Development

• Promote normal growthPromote normal growth Stimulate GH production and secretionStimulate GH production and secretion Enhance GH effectsEnhance GH effects Promote IGF-I production by the liverPromote IGF-I production by the liver

• Promote development and maturation ofPromote development and maturation of Nervous system – promote nerve growth factor (NGF)Nervous system – promote nerve growth factor (NGF) Promote neural branching (synapses)Promote neural branching (synapses) Promote myelinization of nerve fibersPromote myelinization of nerve fibers

• Essential for normal cell division, differentiation, and Essential for normal cell division, differentiation, and maturation in the developing fetus, especially in the brain maturation in the developing fetus, especially in the brain and skeleton and skeleton

Kelenjar paratiroidThe human parathyroid glands, viewed from behind.

Section of human parathyroid. (Reduced 50% from x 960.) Small cells are chief cells; large stippled cells (especially prominent in the lower left of picture) are oxyphil cells. (Reproduced, with permission, from Fawcett DW: Bloom and Fawcett, A Textbook of Histology, 11th ed. Saunders, 1986.)

Parathyroid hormone. The symbols above and below the human structure show where amino acid residues are different in bovine and porcine PTH. (Reproduced, with permission, from Keutmann HT et al: Complete amino acid sequence of human parathyroid hormone. Biochemistry 1978;17:5723. Copyright © 1978 by the American Chemical Society.)

Signal transduction pathways activated by PTH or PTHrP binding to the hPTH/hPTHrP receptor. Intracellular cAMP is increased via G s and adenylyl cyclase (AC). Diacylglycerol and IP3 (1,4,5-InsP3) are increased via Gq and phospholipase C (PLC). (Modified and reproduced, with permission, from McPhee SJ, Lingappa VR, Ganong WF [editors]: Pathophysiology of Disease, 4th ed. McGraw-Hill, 2003.)

Parafollicular cells in the thyroid. (Modified from Poirier J, Dumas JLR: Review of Medical Histology. Saunders, 1977.)

Human calcitonin.

CalciumCalcium

Fungsi KalsiumFungsi Kalsium Fungsi KalsiumFungsi Kalsium

• Pembentukan mineral tulangPembentukan mineral tulangPertumbuhan dan pemeliharaan tulangPertumbuhan dan pemeliharaan tulangGaram hidroksiapatit (hydroxyapatite): Ca10(PO4)6(OH)2Garam hidroksiapatit (hydroxyapatite): Ca10(PO4)6(OH)2

• Pembekuan darahPembekuan darah

• Kontraksi ototKontraksi otot

• ‘‘Second messenger’: Second messenger’: IP3 IP3 End. Ret End. Ret ion Ca ion Ca enzim enzim

• Penglepasan hormon dan neurotransmiterPenglepasan hormon dan neurotransmiter

• Fungsi sarafFungsi saraf

• Pembentukan mineral tulangPembentukan mineral tulangPertumbuhan dan pemeliharaan tulangPertumbuhan dan pemeliharaan tulangGaram hidroksiapatit (hydroxyapatite): Ca10(PO4)6(OH)2Garam hidroksiapatit (hydroxyapatite): Ca10(PO4)6(OH)2

• Pembekuan darahPembekuan darah

• Kontraksi ototKontraksi otot

• ‘‘Second messenger’: Second messenger’: IP3 IP3 End. Ret End. Ret ion Ca ion Ca enzim enzim

• Penglepasan hormon dan neurotransmiterPenglepasan hormon dan neurotransmiter

• Fungsi sarafFungsi saraf

Ca++ vital rolesCa++ vital roles

1.1. Neuromuscular excitabilityNeuromuscular excitability

• Ca++ Ca++ Em Em muscular excitability muscular excitability

• Ca++ Ca++ Em Em muscular excitability muscular excitability

cardiac arrhythmiacardiac arrhythmia

2.2. Excitation-contraction coupling in cardiac & smooth muscleExcitation-contraction coupling in cardiac & smooth muscle

• Ca++ Ca++ myocardial, and smooth muscle contractility (particularly) myocardial, and smooth muscle contractility (particularly)

3.3. Stimulus-secretion couplingStimulus-secretion coupling

• Ca++ entry into secreting cells (endocrine cells, nerve cells) in Ca++ entry into secreting cells (endocrine cells, nerve cells) in response to stimulation response to stimulation secretory product (peptide hormones, secretory product (peptide hormones, catecholamines, neurotransmitters) exocytosiscatecholamines, neurotransmitters) exocytosis

4.4. Blood clottingBlood clotting

1.1. Neuromuscular excitabilityNeuromuscular excitability

• Ca++ Ca++ Em Em muscular excitability muscular excitability

• Ca++ Ca++ Em Em muscular excitability muscular excitability

cardiac arrhythmiacardiac arrhythmia

2.2. Excitation-contraction coupling in cardiac & smooth muscleExcitation-contraction coupling in cardiac & smooth muscle

• Ca++ Ca++ myocardial, and smooth muscle contractility (particularly) myocardial, and smooth muscle contractility (particularly)

3.3. Stimulus-secretion couplingStimulus-secretion coupling

• Ca++ entry into secreting cells (endocrine cells, nerve cells) in Ca++ entry into secreting cells (endocrine cells, nerve cells) in response to stimulation response to stimulation secretory product (peptide hormones, secretory product (peptide hormones, catecholamines, neurotransmitters) exocytosiscatecholamines, neurotransmitters) exocytosis

4.4. Blood clottingBlood clotting

Pengendalian Homeostasis KalsiumPengendalian Homeostasis KalsiumPengendalian Homeostasis KalsiumPengendalian Homeostasis Kalsium

• Pengendalian absorpsi Ca di usus (vit D3)Pengendalian absorpsi Ca di usus (vit D3)

• Pengendalian reabsorpsi Ca di ginjalPengendalian reabsorpsi Ca di ginjalPTH : reabsorpsiPTH : reabsorpsi1,25 DHC : reabsorpsi1,25 DHC : reabsorpsiKalsitonin : reabsorpsiKalsitonin : reabsorpsi

• Pengendalian kalsium tulangPengendalian kalsium tulangPTH & KalsitoninPTH & Kalsitonin

• Pengendalian absorpsi Ca di usus (vit D3)Pengendalian absorpsi Ca di usus (vit D3)

• Pengendalian reabsorpsi Ca di ginjalPengendalian reabsorpsi Ca di ginjalPTH : reabsorpsiPTH : reabsorpsi1,25 DHC : reabsorpsi1,25 DHC : reabsorpsiKalsitonin : reabsorpsiKalsitonin : reabsorpsi

• Pengendalian kalsium tulangPengendalian kalsium tulangPTH & KalsitoninPTH & Kalsitonin

Calcium DistributionCalcium Distribution

Total Calcium Total Calcium

1100 g – 1.5% BW1100 g – 1.5% BW

Bone Calcium Plasma CalciumBone Calcium Plasma Calcium

99% total 1% total99% total 1% total

10 mg/dL-2.5 mmol/l10 mg/dL-2.5 mmol/l

Diffusible Diffusible Nondiffusible Nondiffusible

1.34 mmol/l 1.34 mmol/l 1.16 mmol/l 1.16 mmol/l

59% plasma calcium 59% plasma calcium 41% plasma 41% plasma calciumcalcium

(protein-(protein-bound)bound)

Ionized (Ca++) Complexed to HCO3, citrateIonized (Ca++) Complexed to HCO3, citrate

1.18 mmol/l 0.16 mmol/l 1.18 mmol/l 0.16 mmol/l

50% plasma calcium 9% plasma calcium50% plasma calcium 9% plasma calcium

Bound to Bound to Bound to Bound to

albumin albumin globulinglobulin

0.92 mmol/l 0.92 mmol/l 0.24 mmol/l 0.24 mmol/l

Relation between plasma Ca2+ concentration and PTH response in humans. The set point is the plasma Ca2+ at which half the maximal response occurred. (Modified and reproduced, with permission, from Brown E: Extracellular Ca2+ sensing, regulation of parathyroid cell functions, and role of Ca2+ and other ions as extracellular (first) messengers. Physiol Rev 1991;71:371.)

Formation and hydroxylation of vitamin D3. 25-Hydroxylation takes place in the liver, and the other hydroxylations occur primarily in the kidneys. The formulas of 7-dehydrocholesterol, vitamin D3, and 1,25-dihydroxycholecalciferol are also shown.

Parathormone and 1.25 (OH)Parathormone and 1.25 (OH)22CholecalciferolCholecalciferol

7-dehydrocholesterol 7-dehydrocholesterol cholecalciferol (vit D3)cholecalciferol (vit D3)

25(OH)D325(OH)D3 ProlactinProlactin

PTHPTH

24.25(OH)24.25(OH)22D3D3 1.25(OH)1.25(OH)2 2 D3D3

Intestine Ca++ absorptionIntestine Ca++ absorption Bone resorption Bone resorption Kidney Ca++ Kidney POKidney Ca++ Kidney PO4 4 ionion

reabsorbtion reabsorptionreabsorbtion reabsorption

plasma Ca++plasma Ca++ plasma POplasma PO4 4 ionion

CalcitoninCalcitonin

• Control of secretionControl of secretion

Secreted by the parafollicular cellsSecreted by the parafollicular cells

[Ca++] > 9.5 mg/dl [Ca++] > 9.5 mg/dl calcitonin calcitonin Estrogen Estrogen calcitonincalcitonin Glucagon Glucagon calcitonin calcitonin

CalcitoninCalcitonin

Effects Effects

KidneysKidneys

• Calcitonin membrane receptors on renal tubules cellsCalcitonin membrane receptors on renal tubules cells Calcium reabsorptionCalcium reabsorption Phosphate reabosrption Phosphate reabosrption

Bones Bones

• Calcitonin membrane receptors on osteoclastCalcitonin membrane receptors on osteoclast osteoclast activityosteoclast activity bone resorptionbone resorption Ca and PO4 releaseCa and PO4 release

Blood Blood

• [Ca++][Ca++]

• [PO4] [PO4]

Effects Effects

KidneysKidneys

• Calcitonin membrane receptors on renal tubules cellsCalcitonin membrane receptors on renal tubules cells Calcium reabsorptionCalcium reabsorption Phosphate reabosrption Phosphate reabosrption

Bones Bones

• Calcitonin membrane receptors on osteoclastCalcitonin membrane receptors on osteoclast osteoclast activityosteoclast activity bone resorptionbone resorption Ca and PO4 releaseCa and PO4 release

Blood Blood

• [Ca++][Ca++]

• [PO4] [PO4]

CalcitoninCalcitonin

Prevents bone resorption excess in pregnancyPrevents bone resorption excess in pregnancy

estrogenestrogen prolactinprolactin ++

calcitonincalcitonin 1.25 DHC1.25 DHC

bone resorptionbone resorption

[Ca ++][Ca ++]

++ faster faster ---- inhibit inhibit

Prevents bone resorption excess in pregnancyPrevents bone resorption excess in pregnancy

estrogenestrogen prolactinprolactin ++

calcitonincalcitonin 1.25 DHC1.25 DHC

bone resorptionbone resorption

[Ca ++][Ca ++]

++ faster faster ---- inhibit inhibit

• . Estrogens inhibit secretion of cytokines such as IL-1, IL-6, and TNF, and these cytokines foster the development of osteoclasts.

• Estrogen also stimulates production of TGF-, and this cytokine increases apoptosis of osteoclasts.

• However, it now appears that even small doses of estrogens may increase the incidence of uterine and breast cancer

Total body calcium, an index of bone mass, at various ages in men and women. Note the rapid increase to young adult levels (phase I) followed by the steady loss of bone with advancing age in both sexes (phase III) and the superimposed rapid loss in women after menopause (phase II). (Reproduced, by permission of Oxford University Press, from Riggs BL, Melton LJ III: Involutional osteoporosis. In Evans TG, Williams TF (editors): Oxford Textbook of Geriatric Medicine. Oxford Univ Press, London, 1992.)

Cortisol Cortisol

• Antigrowth effectsAntigrowth effects

Promoting protein breakdownPromoting protein breakdown Blocking the secretion of GHBlocking the secretion of GH Inhibiting growth in long bonesInhibiting growth in long bones

Normal trabecular bone (left) compared with trabecular bone from a patient with

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