Bone Physiology

Structure & Composition of bone

Structure

• specialized connective tissue
  • with minerals within infrastructure
• organic compounds:
  • osteogenic cells
  • osteoblasts
  • osteocytes
  • osteoclasts
• Tissue components of bone
  • Osteoid (major)
    • 30% of total skeleton mass
    • Made up of
      • Organic matrix
        • 90-95% of organic matrix : type 1 collagen fibers
      • Ground substance
        • ECF
        • glycoproteins
        • proteoglycans
          • chondroitin sulfate
          • hyaluronic acid
      • Osteocalcin
        • a vitamin K dependent protein
        • synthesized by osteoblasts at sites of new bone formation
        • binds to hydroxyapatite – participate in
  • Mineral matrix
    • Hydroxyapatite crystals
      • made up of bone salts (calcium & phosphate)
        • crystalline salts deposited in organic matrix
      • long, flat plate
      • Tightly packed around collagen
        • hardens bones
        • bones last longer after death
    • Other ions (conjugate to hydroxyapatite crystals)
      • Na+
      • Mg+
      • K+
      • CO3- (carbonate)

Bone cells (3 types)

• Osteoblasts
  • originate from progenitor cells within osteogenic tissue of the bone
    • arises from mesenchymal precursor cells in bone marrow
  • principal bone forming cell
  • while differentiating (to osteocytes)
    • acquire PTH & Vitamin D receptors
    • surface expression of alkaline phosphatase
    • expression of bone matrix protein genes
      • type 1 collagen
      • osteocalcin
      • osteopontin
      • others
  • Stimulate osteoclast formation and activation
    • via cell surface molecule RANKL
    • Receptor Activator Nuclear factor Kappa B ligand
    • stimulated by
      • Vit D
      • PTH
      • cytokines
        • IL-1
        • IL-6
        • IL-11
      • TNF
• Osteocytes
  • originate from progenitor cells (same as above)
  • mature bone cells
    • derived from osteoblasts
  • occupies lacunae
  • remain trapped within the cortical bone during remodelling process
  • develops multiple processes – canaliculi
    • reach out through lacunae in bone tissue
    • communicate with
      • nutrient capillaries
      • processes of other osteocytes within unit of bone (osteon)
      • processes of surface osteoblasts
  • acts as cellular syncytium
    • permits translocation of minerals in and out of regions of bone removed from surfaces
  • sensors of mechanical loading
  • provide key signals
    • that trigger bone modelling and remodelling
  • responsible for osteocytic osteolysis (see below)
• Osteoclasts
  • orginate from mononuclear phagocytic cells (haemopoietic monocyte lineage)
    • it is a multinucleated giant cell
    • from fusion of several precursor cells
    • bone resorption
      • during growth and skeletal remodelling
      • occupies the surface of bone and erode it
      • lies in Howship’s lacunae
        • dig a cavity into bone
        • at the site of contact with bone, there is a highly folded border – Ruffled border of microvilli

• Bone mineral
  • major form
    • hydroxyapatite crystals of varying maturity
  • minor form
    • amorphous calcium phosphate
      • occurs in regions of active bone formation
      • larger quantity in young bone
      • lacks a coherent x-ray diffraction pattern

Bone mineralization

• Hydroxyapatite crystals are deposited on the collagen layers to produce lamellar bone
• Mineralization requires (secreted in large amounts by osteoblasts)
  • ECF calcium
  • phosphate
  • alkaline phosphatase

Osteocytic osteolysis

• Canaliculi of osteocytes permits exchange of calcium from the interior of bones to exterior
  • to ECF/Blood
  • or from exterior to bone
  • via breakdown of bone
• Remove calcium from mineral crystals (bone, hydroxyapatite) when plasma Ca2+ level falls

Bone Calcification

• Osteoblasts secrete
  • collagen molecules (collagen monomers)
    • wire mesh
  • proteoglycans (ground substance)
    • cement
• Collagen monomers polymerize to form collagen fibers
  • mix with ground susbstance
    • forming osteoid
    • cartilage like material
• Calcium salts deposited in osteoid
• Osteoblasts entrapped in osteoid
  • forming osteocyte
• Calcium salts precipitate on the surface of collagen fibers
  • Form hydroxyapatite crystals
  • Why is hydroxyapatite not formed in normal tissues?
    • Calcium & phosphate in plasma is greater than those required to precipitate
    • Inhibitors present in all tissues
      • Pyrophosphate is inihibiting precipitation of hydroxyapatite in normal tissue
      • If pyrophosphate absent, will have precipitation of calcium in non osseous tissue
        • in arteriosclerosis
        • in old blood clot
      • In bone, osteoblasts secrete substances to inhibit pyrophospahte

Bone remodelling

• Bone resorption & bone deposit
  • at the surface of periosteum & endosteum
  • large volumes of bones are removed and replaced
    • continuous process
    • completion of full remodelling cycle lasts 6 months
    • except for growing bones, rate of deposition = absorption
• Does not absolutely require hormones
  • but influences remodelling – like PTH
• Bone remodelling unit/ Basic molecular unit (BMU)
  • osteoblasts
  • osteoclasts
  • macrophages
• Bone remodelling process initiated by osteoclasts
• Bone resorption
  • by osteoclasts
    • forms an adhesive ring – seals off an area
    • develops an elaborately invaginated plasma membrane structure – Ruffled border
      • Ruffled border villi secretes:
        • Citirc acid & lactic acid
          • from mitochondria & secretory vesicles
          • dissolves bone mineral/salts
        • Proteolytic enzyme/proteases (cathepsin K)
          • breaks down bone matrix
      • products endocytosed by osteoclasts and released into the interstitial fluid/blood
        • bone matrix
        • crystals
  • releases IGF-1 from bone matrix
    • stimulates osteoblast proliferation and differentiation
  • after osteoclasts done the resorption
    • macrophages phagocytose debris of old bone
    • clears the site before bone formation takes place
• Bone formation
  • to increase bone strength and to repair injured bone
  • new bone deposits by osteocytes
  • Factors involved
    • local concentration of calcium & phosphate
      • regulated by
        • PTH
        • Vit D
          • helps to maintain intestinal absorption of minerals and ensure adequate supply of calcium & phosphorus
        • Calcitonin
    • matrix proteins
    • alkaline phosphatase
  • goes to site of resorption when osteoclasts release IGF-1 from bone matrix

Regulation of bone remodelling

Regulation of bone remodelling

• Calcium homeostasis in blood (by hormones)
  • Parathyroid hormone (PTH)
    • both resorption and formation
    • increases proliferation of osteoclasts
    • activates already existing osteoclasts
    • increases bone resorption
      • hyperparathyroidism
        • increased osteoclastic activity
        • xray – extensive decalcification
        • multiple fractures of the weakened bones from slights trauma
    • PTH receptors in osteoblasts only. Osteoclasts have none.
  • Active form of vitamin D (DHCC)
    • promotes bone calcification
    • increased absorption of calcium & phosphate from the intestines
    • enhanced mineralization of bone
    • promote development of osteoclasts from precursor cells (act on bone cells)
    • vitamin D receptors in both osteoblasts and osteoclasts
  • Calcitonin
    • inhibits osteoclastic activity
    • decreases formation of new osteoclasts
    • inhibits bone resorption
    • increases bone deposition
  • Oestrogen
    • slow bone resorption
    • decreases the formation of osteoclasts
      • oestrogen deficiency (menopause)
        • activation of new bone remodelling sites
        • exagge
          ration of imbalance between bone formation and resorption
        • increases osteoclast recruitment and activity
        • increases apoptosis of osteoblasts
        • increases remodeling at trabecular bone (vertebral fractures common)
• Mechanical & gravitational forces acting on the skeleton
• By RANKL – ligand

NETT EFFECT

• Bone resorption
  • PTH
    • osteoblast also secretes IL-6 – more resorption
    • inhibits collagen synthesis by osteoblasts
  • DHCC
    • both PTH & DHCC stimulate osteoblasts to secrete [M-CSF] & RANKL that causes osteoclast precursor cell proliferation
    • then differentiate into osteoclasts
    • fuse to form multinucleated osteoclasts
• Bone formation
  • oestrogen
    • slows down resorption
• Inhibit bone resorption
  • Calcitonin

• Osteoclast activation
  • RANKL + RANK
• Osteoclast inhibition
  • RANKL + OPG

Osteon (Haversian system)

Elongated tube of bone matrix with concentrically arranged lamellae of bone surrounding a canal containing blood vessels, nerves and lymphatic. The canal is lined by endosteum.

Haversian canals via Volksmann’s canal, communicates with:

• one another
• periosteum
• marrow cavity

Volkmann’s canal:

• no lamellae around it
• lined by endosteum

Arrangement of collagen fibers – gives extra strength (withstand torsion stress)

• In a particular lamellae
  • parallel and run in one direction
• In adjaacent lamellae
  • run in opposite direction

Ossification/Osteogenesis

Refer foundation 1 notes

 
Endochondral ossification

Starting from foetal skeleton, if it consist of:

• Fibrous membranes
  • undergo Intramembranous ossification
  • skull cap and clavicle
    • fibrous connective tissue membrane have messenchymal cells
    • differentiate into osteoblast forming ossification center
      • secretes osteoid
      • forming non-calcified bone
    • blood vessels grow into osteoid
      • osteoblasts become osteocytes
      • osteoid calcified
    • covering messenchyme vascularize and form periosteum
    • external compact bone formed
    • internal spongy bone formed
• Hyaline cartilage
  • undergo Endochondral ossification
  • All bones except skull cap and clavicle
    • bone collar formation
    • cartillage calcified
      • then destroyed
    • periosteal bud invades (blood vessel)
    • osteoblasts reach the center
    • via the blood vessels
    • osteoid formed
    • medullary cavity formed
    • osteoid calcified
  • primary center – diaphysis
  • secondary center – epiphysis

Bone growth

• Growth in length (at adulthood, cartillage cell growth stops and epiphyseal plate becomes thinner & disappear)
• Growth zone
• cartilage cells multiply (mitosis)
• Transformation zone
• cartilage cells enlarge
• matrix calcified
• cartilage cells die
• Osteogenic zone
• osteoblasts secrete osteoid
• osteoclasts remove the calcified cartilage
• Growth in width
• periosteal osteoblasts form new bone on the surface
• increases width
• endosteal osteoclasts remove bone from within
• maintains marrow cavity

Bone repair

• Blood clot forms (hematoma)
• bone cells die
• dead tissue removed
• Fibroblasts invade
• collagen and cartilage formed (soft callus)
• Osteoblasts invade
• Cartilage removed
• replaced by bone (bondy callus)
• Excess bone is removed
• Bone is remodelled