9/30/1999

Regulation of the skeletal massthrough the life span

Regulation of the skeletal massthrough the life span

9/30/1999

Functions of the skeletal systemFunctions of the skeletal system

n Mechanical protection– skull

n Movement– leverage for muscles

n Mineral metabolism– calcium store

n Erythropoiesis– red blood cells in bone marrow

9/30/1999

Changes in the skeletal systemwith ageChanges in the skeletal systemwith agen Early development

– fetal, infancy, childhood:– statural skeletal growth

n Midlife– hypertrophic growth– reparative growth

n Old age– hypertrophic growth– impaired reparative growth

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Skeletal growth by elongationand change in shape

Skeletal growth by elongationand change in shape

Growth during fetal development,infancy, childhood and

adolescence

9/30/1999

Early development :endochondral bone growthEarly development :endochondral bone growthn Endochondral growth and ossification

– long bones

n Intramembranous ossification– flat bones

n Growth process– cartilage bone model formed– chondroblasts proliferate– create rough bone shape

9/30/1999

Early development :endochondral bone growthEarly development :endochondral bone growthn Endochondral growth and ossification

– chondrocytes differentiate– secrete matrix

< proteoglycans

– polar regions grow more actively– cells hypertrophy in central region– cells express alkaline phosphatase– mineral matrix kills cells

9/30/1999

Early development : endochondralbone growthEarly development : endochondralbone growth

n Endochondralgrowth andossification– space with dead

cells invaded byblood vessels

– debris cleaned up byosteoclasts

– invasion byosteoblasts

– bone formation< diaphysis< epiphysis

9/30/1999

Epiphysealgrowth zoneEpiphysealgrowth zonen Zone of resting

cartilage(geminative layer)

n Proliferative zonen Hypertrophic zone

– dying cartilage– invasion of blood

vessels– osteoclast clean-up

n Mineralization byosteoblasts

9/30/1999

What is needed for early bonegrowth?What is needed for early bonegrowth?n Hormonal guidancen Adequate nutritionn Mechanical stimulation

9/30/1999

Hormonal mediation of earlybone growthHormonal mediation of earlybone growthn No involvement of growth hormonen Important role of insulin

– carbohydrate and amino acid uptake– carbohydrate metabolism for ATPs– cell proliferation

n Important role of IGF-II (fetal) and IGF-I(postnatal)– cell proliferation– protein synthesis

9/30/1999

Hormonal mediation of earlybone growthHormonal mediation of earlybone growthn Important role of thyroid hormones

(thyroxine> triiodothyronine)– growth of muscle and long bones– maturation of bones and other tissues– antagonism of insulin and IGF-I action

n Important maturational role of cortisoln Insulin and T4 act on gene expressionn Insulin and T4 induce IGF synthesis

9/30/1999

Hormonal mediation ofchildhood and adolescent bonegrowth

Hormonal mediation ofchildhood and adolescent bonegrowth

n Control by growthhormone and IGF-I

n GH receptors andaction ongerminative cells– differentiation of IGF-

I receptors

n IGF-I hepatic and inbone– action on

proliferative cells

9/30/1999

Hormonal mediation ofchildhood and adolescent bonegrowth

Hormonal mediation ofchildhood and adolescent bonegrowth

n Control by estrogen in both genders– receptors on osteoblasts– suppression of osteoclast action– release of IGF-I by osteoblasts– closure of EGZ

9/30/1999

Nutritional mediation of earlybone growthNutritional mediation of earlybone growthn Abundant nutrition is requiredn Maternal circulation provides

– energy– specific nutrients (calcium, amino acids)

n Inadequate nutrition results in stuntingn Concerns

– heavy maternal exercise– undernutrition during infancy

9/30/1999

Mechanical modulation of bonegrowthMechanical modulation of bonegrowth

n Immature or vowenbone– coarse-fibered– collagen fibers show

no specialorientation

n first bone thatdevelops– in ontogeny– after a break

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Mechanical modulation of bonegrowthMechanical modulation of bonegrowth

n Mature or lamellar– collagen fibers show

special orientation inalignment withmechanical forces

n Rough cartilagebone model isshaped to withstandprevailing forces

9/30/1999

Lamellar boneLamellar bone

n Cortical (compact) bone– shafts (diaphyses) of long bones– surface of flat bones

n Trabecular (spongy or cancellous) bone– ends and interior of long bones

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Cortical (compact) boneCortical (compact) bonen 80% of skeletal massn Haversian systemn Concentric layers of

mineraln Endosteal cells detect

strainn Blood vessel and

nerve &communicating canals

n Density and structureconfer strength

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Trabecular, spongy or cancellousboneTrabecular, spongy or cancellousbone

n 20% of skeletalmass

n More porousn Lamellae are

aligned inparallel withstresstrajectories

9/30/1999

Trabecular, spongy or cancellousboneTrabecular, spongy or cancellousbone

n Lamellae arealigned in parallelwith stresstrajectories

n In appendicularskeleton more thanin axial

n Wolff’s law

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Mechanical guidance oflongitudinal bone growthMechanical guidance oflongitudinal bone growth

n The shape of thebone changes asthe bone grows insize (modeling)

n Changes in shapeare guided bychanges inmechanical loadingof the growing bone

9/30/1999

Hypertrophic bone growth inadulthood

Hypertrophic bone growth inadulthood

Increases in bone density andbone geometry in response to

changes in stress

9/30/1999

Hypertrophic bone growthHypertrophic bone growth

n occurs when bone is deformed(strained) in response to mechanicalforce

n Strain produces a force (stress) withinthe bone

n Bone will increase in density andchange configuration so it can meet theforce without getting deformed

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Mechanical forces producingstrainMechanical forces producingstrain

n tensionn compressionn shear

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Mechanical forces producingstrainMechanical forces producingstrain

n Magnitude ofstrain

n Capacity ofbone stressresistance

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Hypertrophic response in boneHypertrophic response in bone

n Increases in bone mineral densityn changes in lamellar geometry so that they are

aligned with stress trajectories (Wolff’s law)

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Hypertrophic response in boneHypertrophic response in bone

n occurs throughmodeling within abone metabolic unit(BMU)

n stages– quiescence– activation– resorption– reversal– formation– quiescence

9/30/1999

Hypertrophic response in boneHypertrophic response in bone

n mediated by– activation by stress of osteoclasts– secretion by osteoclasts and monocytes of

cytokines IL-1, IL-6, prostaglandin E2– removal of unstressed parts of bone– secretion by osteoblasts of IGF-I, TGFbeta,

PGE , osteocalcin, BMPs– bone formation

9/30/1999

Reparative growth of the boneand mineral homeostasis

Reparative growth of the boneand mineral homeostasis

Maintenance of bone massthroughout life

9/30/1999

Reparative growth of the boneReparative growth of the bone

n bone is continuously remodeled formetabolic maintenance (internalremodeling)

9/30/1999

Metabolic function of the boneMetabolic function of the bone

n bone serves as a reservoir of calcium inthe body

n calcium is withdrawn from the bone– when it is needed to maintain blood

calcium balance– when the hormonal environment favors

bone resorption– when bone is insufficiently loaded

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Minerals in the bodyMinerals in the body

n Ca– plasma constituent– excitability of muscle, nerve cells– intracellular signalling– mineral component of bone (99% ot total Ca)

n Plasma and bone calcium regulatedseparately

12/1/1998

Organs that participate in plasmacalcium homeostasis :Organs that participate in plasmacalcium homeostasis :

n Calcium issecured fromintestine, boneor kidney

n Plasma Catakesprecedence tobone mineralbalance

9/30/1999

Hormones that control internalremodelingHormones that control internalremodelingn Parathyroid hormone

– increases plasma calcium– acts on

< bone (resorption)< intestine (Ca absorption)< kidney (vitamin D synthesis and Ca

reabsorption)

12/1/1998

Hormonal controlHormonal control

n PTH action onbone– increases

boneresorption byacting first onosteoblasts

– Osteoblastsactivateosteoclasts

12/1/1998

Hormonal controlHormonal control

n PTH action onkidney– stimulates

synthesis ofvitamin D3

– vitD3 stimulatessynthesis ofintestinal Catransport proteins

– increases Ca andphosphatereabsorbtion

12/1/1998

Vit D3Vit D3n sunlight forms

cholecalciferoln dietary source od

D3 and D2n Liver makes 25-

(OH)VitD3n Kidney makes

1,25-(OH)2VitD3

12/1/1998

Hormonal controlHormonal control

n PTH action onthe intestine– VitD3

stimulatessynthesis oftransportprotein

– Increasedintestinalabsorbtion ofCa

2/25/99

Plasma calciumPlasma calcium

n Regulated range– 8.6-10.2 mg/dl– 3 - 8 mEq/l

n two counter-regulating hormones– Parathyroid hormone– Calcitonin

2/25/99

Regulation of plasma calciumRegulation of plasma calcium

n Parathyroidhormone– released when

plasma Ca is low– increases plasma

Ca

n Calcitonin– released when

plasma Ca is high– decreases plasma

Ca

2/25/99

Hormonal controlHormonal control

n Important role of estrogen in preventing– osteoclastic bone resorption

< inhibits production of resorptive cytokines– IL-1– IL-6– TNF– and PGE