PP17 Pre and Postnatal Skeletal Development 2

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PP17Pre and Postnatal Skeletal Development 2

• Chapter 8 pg 137-147
• ANS 3043
• University of Florida
• Dr. Michael J. Fields

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Bone Formation

• Osteogenesis
• Occurs in pre and postnatal life by
  transformation of cartilage into bone
• Types of Bone Formation
• Endochrondal ossification requires a cartilage
  template
• Intramembranous ossification occurs in absence of
  cartilaginous template

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Bone Formation

• Embryonic Origin of Skeleton
• Condensation of mesenchymal cells, which
  differentiate in to chondroblasts
• Axial skeleton forms from sclerotome
• Appendicular skeleton is from lateral plate
  mesoderm
• Progenitor cells migrate to sites of future bone
  development
• Undergo differentiation into specific cell types
• Dependent on interaction of mesenchymal and
  epithelial cells
• Involves up-regulation of numerous growth and
  signaling factors
• Mesenchymal condensations determine site and
  shape of bone

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Somites
Vertebral column
Skeletal limbs
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• Appendicular skeleton is from lateral plate
  mesoderm

Skeletal limbs
Myotome
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(No Transcript)
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Endochondral Growth

• Endochondral (Cartilage) Growth Long bone
  development
• Results in cartilage deposition at the epiphyseal
  plate
• Zones of growth plate from epiphysis to diaphysis
• Zone of Growth (Reserve Zone, Resting Zone, Stem
  Cell Zone)
• No vascular supply
• Chondrocytes line up in columns and produce
  extracellular matrix molecules
• Includes various types of collagen and
  proteoglycans
• Pushes epiphysis away from the diaphysis

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Bone Development Fetal and Postnatal
Chondrocytes
Growth Hormone/IGF
Proliferate stacking on top of each other
1.
2.
Bone grows
3.
4.
Cartilage
5. Apoptosis
6.
7.
8.
Hypertrophy
9.
Ossification
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Endochondral Growth

• Zone of Cartilage Transformation (prehypertropic
  and hypertropic zones)
• Hypertrophy of chondrocytes
• Produce additional molecules for extracellular
  matrix including different types of collagen and
  proteins that contribute to mineralization of
  matrix
• Mature chondrocytes move away from nutrition and
  die leaving behind calcified matrix

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Endochondral Growth

• Zone of Ossification
• Development of new bone due to invading
  capillaries and osteoblasts
• Osteoblasts move into network and deposit organic
  matrix
• Osteoid Osteoblast differentiation
  ossification
• Connection of adjacent osteocytes by cytoplasmic
  threads
• Leads to development of spongy bone near ends of
  diaphysis
• Appositional growth at walls of bone shafts and
  metaphysis
• No definite endpoint to this type of growth

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Endochondral Growth

• Continued development of epiphyseal plate
• Rate of cartilage growth greater than rate of
  oteoblast invasion
• Termination of long bone growth
• Growth finishes when the cartilage of the
  epiphyseal plate is eliminated
• Fusion of epiphysis and diaphysis (primary and
  secondary points of ossification)
• Influenced by hormones, nutrition, minerals and
  chronological age

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Endochondral Ossification

• Replacement of cartilage with bone
• Chondrocytes lay down intercellular matrix of
  cartilage model
• Serve as a template for ossification and eventual
  development of bone
• Hypertrophy of chondroblasts, which eventually
  differentiate into chondrocytes (mature
  cartilage)
• Fibroblasts produce collagen
• Osteoblasts/Osteocytes produce bone

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Endochondral Ossification

• Cartilage model enlarges with continued secretion
  of collagen matrix
• Interstitial cartilage growth (within)
• Appositional cartilage growth (outside)
• Development of perichondrium (sheath that
  surrounds cartilage)
• Chondrocytes continue to enlarge and mature
• (Chondrocytes are mature cartilage cells that
  secrete cartilage)

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Endochondral Ossification

• Calcification of middle of cartilage model
• Begins to break up leaving cavities
• Nutrients cant reach chondrocytes so they die
  (apoptosis) and disintegrate
• In conjunction with internal changes changes to
  perimeter of diaphysis occur
• Perichondrium (outside layer turns into
  periosteum)
• Coincident with initial vascular invasion
• Osteoblast migration from outer regions into
  center region of development
• Formation of bone on perimeter of diaphysis to
  form bone shaft

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Endochondral Ossification

• Development of primary ossification center
• Calcified cartilage matrix broken down by action
  of osteoclasts results in replacement of
  calcified cartilage with bone
• Development of spongy bone from center of bone
  outward
• Initiation of bone ossification
• Continued growth of cartilage model
• Proportion of total cartilage decreases as the
  fetus gets older
• Reabsorption of spongy bone results in bone
  marrow cavity formation (due to osteoclasts
  increasing diameter of cavity)

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Endochondral Ossification

• Near birth secondary center of ossification forms
  in the center of the epiphysis
• Osteoblasts replace cartilage with spongy bone
• Articular cartilage remains on surface of each
  epiphysis to form joints

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Osteoclasts eat away at bone
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Endochondral Ossification

• Epiphyseal plate thin cartilage layer between
  epiphysis and diaphysis
• Allows for continued long bone growth after birth
• Involves action of chondrocytes (cartilage) and
  osteoblasts
• Growth of cartilage on epiphyseal plate side of
  growth plate
• Ossification of cartilage on diaphyseal side of
  growth plate
• Results in increased length of long bone

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Bone Development Fetal and Postnatal
Bone Formation
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Bone Development Fetal and Postnatal
Reabsorbtion of Spongy Bone
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Intramembranous Growth

• Bone formation as a replacement of connective
  tissue, but in absence of cartilage
• Mesenchyme cells differentiate directly into
  osteoblasts (produce collagen fibers and bone
  matrix)
• Oteoblasts diffentiate into osteocytes to produce
  bone (Figure 8.5)
• Bone changes from spongy to one of few cavities
  surrounded by compact bone
• Typical of flat bones skull, mandible and
  clavicle

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Outside
______________
Osteocytes
Osteon (circle)
Inside
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Intramembranous Growth

• Increased diameter occurs by appositional growth
  (Figure 8.6)
• Osteoblasts from periosteum deposit new bone
  matrix in the periosteum
• Note for next slide
• Greatest growth in areas surrounded by periosteal
  blood vessels
• New osteons produced due to concentric deposition
  of bone and formation of osteocytes which
  contribute to compact bone and increased diameter

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Bone Development Fetal and Postnatal
Osteon formation
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Bone Reabsorption

• Removal of bone by osteoclasts at inner surface
  and enlarging medullary cavity
• Osteoclasts large cells with greater than 50
  nuclei
• Develop from mononuclear cells that proliferate
  in marrow with fusion taking place near site of
  action
• Osteoclasts make contact with bone in region know
  as ruffled border
• Degrades inorganic into soluble fraction
• Creates acidic environment (decrease pH) with
  carbonic anhydrase Type II

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Bone Reabsorption

• Osteoclasts
• Results in mobilization of minerals
• Important in regulating chronic concentrations of
  serum minerals
• Also degrades organic portion of bone with
  enzymes
• Growth of bone is a balance of appositional
  growth and resorption
• Sum of the two determine net bone deposition
• If resorption exceeds formation, bone mass
  decreases (older animals)
• Marrow cavities formed as a result of osteoclasts
• Red marrow primary blood cell forming organ in
  adult
• (found in spongy bone epiphysis, sternum, ribs,
  vertebrae)
• Yellow marrow composed mostly of adipose tissue

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Bone Development Fetal and Postnatal
Osteoclasts
Action of osteoclasts in bone resorption BL
basolateral domain CAII carbonic anhydrase
II CpK cathepsin K FSD functional secretory
domain RB ruffled border RL resorption
lucanae SZ sealing zone
Enzyme-acidic Ph


HCL breaks down bone and releases Ca
Bone
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Bone Remodeling

• Structural changes that occur to bone throughout
  lifetime of individual
• Bone resorption (osteoclasts) and formation
  (osteoblasts) net bone depostion
• Can be extensive with 18 of mineral component of
  some some bones replaced a year
• Femur head can be replace 2-3x per year
• Most bone remodeling occurs within spongy bone
• Compact bone is static

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Bone Remodeling

• Bone mass reaches cumulative plateau of growth
  curve
• Remains relatively constant
• Formation and reabsorption in appropriate balance
• Necessary for bone to remain functionally
  constant
• Allows bone to adapt to growth and in response to
  stress (heavy stress thicker, stronger bones)
• Due to osteoblasts depositing bone
• Possibly mediated through osteocytes that serve
  as mechano-receptors
• Increased muscle growth results in increased bone
  growth/mass

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Bone Remodeling

• Old calvary riders had larger bones because
  stress resulted in greater turnover (found in
  archeological digs)
• Arikara Tribe along Missouri River in South
  Dakota (1850)
• Great corn farmers (women)
• Bone mass of left leg increased over four
  centuries as left leg was jused to pus off with
  while working in the fields (Sports favors right
  leg)
• Bone mass of right arm increased as right arm was
  used to support a rifle (men)
• Early men hunted with a bow and arrow, which
  resulted in balanced bone

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Bone Remodeling

• Measuring bone remodeling
• Biochemical markers (serum alkaline phosphatase
  and osteocalcin)
• Histomorphometric (structure and cell function)
• Inject with fluorochrome products, which bind to
  calcium sites of mineralization
• Subject bone section to histological analysis
• Allows measurement of mineral apposition, new
  bone formation and other anatomical measurement

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Bone Remodeling

• Measurement allows for investigation into the
  developmental changes as well as the effect of
  dietary and hormonal changes on bone development

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Bone Repair

• Fracture results in disruption of blood supply to
  bone
• Osteocytes begin to die due to hypoxia, leading
  to necrosis of periosteum and marrow
• Hemorrhage leads to clots
• Fibrous mass formationcontaining numerous growth
  factors
• Cartilage formation from osteoblasts derived from
  peri/endosteum
• Boney union of fracture (replace disc with bone,
  vascularization, cartilage from osteoblast
  invasion)
• Due to slow accretion of new bone, fractures
  require a long time to heal

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Factors Affecting Bone Growth

• Endogenous
• Parathyroid hormone (PTH)
• Increases blood calcium
• Increased osteoclast activity
• Ca released from bone
• Decreased osteoblast activity
• Increased kidney and GI tract Ca reabsorption
• Regulates phosphorous metabolism of bone

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Factors Affecting Bone Growth

• Calcitonin
• Decreases blood calcium
• Inhibits osteoclast activity
• Decreased bone reabsorption
• Increased osteoblast activity
• Thyroid Hormones
• Hyperthyroidism
• Increases bone reabsorption
• Hypothyroidism Supplement T4
• Increases chondrocyte activity (suggests that
  Thyroid Hormone is necessary for normal bone
  growth

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Bone Development Fetal and Postnatal
Hormone Action
Calcitonin (-) Decreased osteoclast Decreased
calcium
Parathyroid () Increased osteoclast Increased
calcium
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Factors Affecting Bone Growth

• Glucocorticoids
• Acts synergistically with Insulin-like growth
  factors (IGFs) to enhance bone growth
• Excess causes bone resorption
• Sex Steroids
• Testosterone (male)
• Enhances bone growth at epiphyseal plate
• Excess hastens rate of bone maturation (puberty)

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Factors Affecting Bone Growth

• Estrogen (female)
• Enhances growth until epiphyseal plate closure
• Excess hastens rate of bone maturation
• More effective in mediating closure of epiphyseal
  plate than testosterone
• Castrates retain ability for long bone growth
  than intact animals
• Does not occur indefinitely (gelding evenutally
  stops growing)

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Factors Affecting Bone Growth

• Vitamin D (mostly from sunlight)
• Increases blood calcium (provides calcium for
  bone formation)
• Deficiency (lack of sun) faulty calcium
  reabsorption
• Improper bone ossification
• Rickets in young adults in growing individuals
• Bone softening in adults
• Northern latitudes show insufficient sunlight
  during winter
• Light skin reabsorbs more, dark skin absorbs less
  
• Use stores of Vitamin D in the liver
• Law requires Vitamin D in milk
• Dogs/Cats (carnivores) do not synthesize Vitamin D

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Factors Affecting Bone Growth

• Vitamin C
• Deficiency osteocollagenous fiber destruction
• Decreased organic matrix production
• Known as scurvy (missing teeth due to
  disappearance of fibers that held teeth)
• Oranges are rich in Vitamin C
• Vitamin A
• Deficiency abnormal bone matrix synthesis
• Poor skeletal growth and remodeling

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Factors Affecting Bone Growth

• Exogenous Factors
• Nutrition
• Proper mineral balance in diet is important for
  proper bone growth
• Calcium and Phosphorous (humans have an abundance
  of phosphorous)
• Decreased skeletal growth and development with
  poor nutrition
• Increased importance in young growing animals

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Factors Affecting Bone Growth

• Age
• Typically not a problem in most farm animals
• More likely in horses and companion animals
• Bone strength decreases with age when
  reabsorption is greater than formation
• Osteoporosis in women (menopause) decreased
  estrogen resulting in decreased calcium
  absorption in bone
• Gender
• Estrogen initiates closure of epiphyseal plate
  sooner than testosterone, which decreases overall
  long bone growth
• Castrates gt Males gt Females

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Factors Affecting Bone Growth

• Exercise
• Increased exercise can increase bone density
• Negative effect if done in excess and without
  adequate mineral balance
• Caution must be followed as to where during
  skeletal development and how much

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Bone Development Fetal and Postnatal
Greater exercise
To much exercise - breaks, splints - dog sleighs
- children
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Bone Development Fetal and Postnatal
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Bone Development Fetal and Postnatal