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
9/30/1999
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
9/30/1999
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
9/30/1999
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
9/30/1999
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
9/30/1999
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
9/30/1999
Mechanical forces producingstrainMechanical forces producingstrain
n tensionn compressionn shear
9/30/1999
Mechanical forces producingstrainMechanical forces producingstrain
n Magnitude ofstrain
n Capacity ofbone stressresistance
9/30/1999
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)
9/30/1999
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
2/25/99
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