Bone Response to Damage

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Introduction

Bone is a hard, highly specialised connective tissue
Consists of interconnected cells embedded in a calcified, collagenous matrix
Living, dynamic, responsive tissue, growing and remodelling throughout life
Pathogenesis of many bone diseases is complex
- May involve genetic defects, diet or infection or a combination of these
Function:
- Support/protection
- Movement
- Stem cell storage
- Mineral storage

Normal structure

Microscopic bone (Courtesy of RVC Histology images)

Cells
- Osteoblasts, osteocytes, chondroblasts and chondrocytes are derived from stromal fibroblastic system (osteoprogenitor cells); osteoclasts from haematopoietic system
- Ischaemia and hypoxia favour development of cartilage
- High oxygen tension and good blood supply favour bone development
- Osteoblasts
  - Mesenchymal cells
  - Arise from bone marrow stroma
  - Histologically:
    - Plump and cuboidal when active
    - Basophilic cytoplasm
    - When inactive - less cytoplasm -> flattened
  - Produce bone matrix = osteoid - uncalcified
    - Homogeneous substance
    - Stains light pink with H&E
  - Cell membranes are rich in alkaline phosphatase (ALP)
    - Possibly involved in pumping calcium across membranes
  - Promoted by growth factors
  - Have receptors for PTH
    - They contract in response -> space for osteoclasts to attach
- Osteocytes
  - Osteoblasts that have become surrounded by mineralised bone matrix
  - Occupy cavities called lacunae
  - Contact osteoblasts and each other with cytoplasmic processes
    - Reach through canaliculi in mineralised bone matrix
  - Regulate composition of bone fluid
- Osteoclasts
  - Histologically:
    - Large, often multinucleated cells
    - Acidophilic cytoplasm
  - Derived from haematopoietic stem cells
  - Responsible for bone resorption
    - Firstly dissolve mineral followed by collagen
    - Use brush border for this
  - Sit in bone surface depression - Howship's lacuna
  - Do not have receptors for PTH
  - Have receptors for calcitonin
    - Involute their brush border in response
    - Detach from bone surface
  - Respond to vitamin D by increasing their numbers and activity (parathyroid independent)
Matrix:
- Osteoid
  - Type I collagen forms the backbone of the matrix (90%)
    - Molecules in staggered rows
  - Non-collagenous protein forming amorphous ground substance (10%)
- Mineral
  - Crystalline lattice of calcium phosphate and calcium carbonate
  - Also contains Mg, Mn, Zn, Cu, Na, F
  - Accounts for 65% of bone

Bone organisation

Patterns of collagen deposition:
- Woven bone:
  - "Random weave" which is only a normal feature in the foetus
  - Coarse collagen fibres
  - Later removed by osteoclasts and replaced by lamellar bone
  - In adults it is a sign of a pathological condition (e.g. fracture, inflammation, neoplasia)
- Lamellar bone:
  - Orderly layers which are much stronger than woven bone
  - Fine collagen fibres in concentric or parallel laminae
  - Two main types:
    - Compact bone (cortical)
      - Forms 80% of total bone mass
      - Consists of cells and interstitial substance - 30% ossein (type of collagen) and 70% minerals, especially calcium phosphate
      - Forms the shell of long bone shafts - contain Haversian systems
    - Cancellous bone (spongy or trabecular)
      - Made up of plates, tubes or bars arranged in lines of stress
      - In vertebrae, flat bones and epiphyses of long bones
      - Contains no Haversian systems
- Laminar bone
  - Formed on periosteal surface of diaphysis
  - Accomodates rapid growth of large dogs and farm animals
  - Plates of woven bone from within the periosteum
  - Concentric plates
  - As it forms, it fuses with the bone surface

Periosteum and blood supply

Periosteum
- Specialised sheath of connective tissue covering bone except at the articular surfaces
- Loosely attached except at tendon insertions and boney prominences (associated with major blood vessels penetrating bone)
- Histologically:
  - Outer layer - fibrous for support
  - Inner layer - osteogenic
    - Contains osteoblasts and osteoprogenitor stem cells in young animals and in adults with fractures or disease
- Rich supply of nerves and lymph vessels
- Damage to periosteum:
  - Invokes a hyperplastic reaction of the inner layer
  - Is painful
  - Exostoses can remodel or remain
- Lifting of periosteum:
  - Causes new bone formation below
- Circumferential incision (e.g. during fracture)
  - Longitudinal bone growth results
  - May be only on one side where periosteum is damaged
    - Used by surgeons to treat angular limb deformities
Blood vessels
- Nutrient, metaphyseal, periosteal arteries
- Normal flow of blood from medulla to periosteum due to higher pressures in medulla
- Young animals have greater blood supply

Endosteum lines the marrow cavity

Bone development

Two main types of bone development:
- Endochondral ossification (cartilage model)
  - Long bones mainly - physis and metaphysis
  - Mesenchymal cells differentiate into chondroblasts
    - Produce scaffold of mineralised cartilage on which osteoblasts deposit bone
  - Vascularised
  - Developed centres of ossification
    - Primary (diaphyseal)
    - Secondary (epiphyseal)
- Intramembranous ossification
  - Flat bones mainly (e.g. skull), shaft of long bones
  - Mesenchymal cells differentiate into osteoblasts
  - No cartilage precursor template

Physis (Growth plate)

Growth plate (Image sourced from Bristol Biomed Image Archive with permission)

Growth plate magnified(Image sourced from Bristol Biomed Image Archive with permission)

Originates from the cartilage model that remains only at the junction of the diaphyseal and epiphyseal centres

Cartilage of metaphyseal growth plate is divided into: (from right to left on the magnified image)
- - Resting (reserve) zone
- - Proliferative zone
- - Hypertrophic zone

Site of many congenital or nutritional bone diseases in the growing animal
Open in neonates and growing animals
- Chondrocyte proliferation balances cell maturation and death
Closes and ossifies at maturity
- Regulated by androgens
If growth teporarily stops -> layer of bone seals the growth plate -> moves into metaphysis when growth resumes -> forms Harris lines

Bone resorption

Mediated by two hormones:
- Parathyroid hormone (PTH)
  - Produced by chief cells in the parathyroid glands in response to decreased serum calcium
  - In response, osteoclasts increase in number and resorb mineralised matrix - increase Ca in blood
- Calcitonin
  - Produced by C-cells in the thyroid glands in response to increased serum calcium
  - Inhibits osteoclasts

Bone dynamics

Bone growth and maintenance of normal structure are directly related to mechanical forces
Mechanical forces generate bioelectrical potentials (piezoelectricity)
- These potentials strengthen bone
- Inactivity reduces the potentials -> bone loss

In neonates:
- Bone growth predominates
- Modelling is important
In adults:
- Formation of bone is balanced by resorption - remodelling
- Continues throughout life under the influence of hormones and mechanical pressure
- Bone resorption may exceed formation in pathological states (hormonal, trauma, nutritional) or in old age and disuse

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