Rheumatology

Basic sciences

Introduction

Basic Joint Anatomy and Physiology

Different joint configurations

  • Plane - the articular surfaces are more or less flat e.g. carpal joints
  • uniaxial pivot or hinge joints e.g. the ankle is a hinge joint and the atlantoaxial is a pivot joint
  • biaxial e.g. Metacarpophalangeal joint
  • Multiaxial e.g. hip is a ball and socket joint

Connective tissue

Connective tissue is what holds us together and makes up organs, bones, eyes, muscles etc otherwise we would be rather shapeless blobs. There is much in common between different tissue types. A collection of differing cells which produce an extracelullar matrix of fibrous proteins with differing properties and an amorphous ground substance. Important components include

  • Collagen - thick, high tensile strength non branching protein
  • Elastin - fibres which can stretch and return to their normal size. Useful for distensibility e.g. bladder, aorta, lung tissue
  • Reticular fibres - form a web like net which is useful acting as a sieve e.g. filtering blood cells in the haemopoietic system
  • Laminin
  • Fibronectin
  • Ground substance

Cells

    There is a great deal of interchangeability between cells of the connective tissue family such as

    • Fibroblasts - produce collagen
    • Chondroblasts - form cartilage
    • Osteoblasts - lay down bone
    • Adipose cells - fat storage
    • Smooth muscle cells

    The differentiation depends upon

    • Cytokines
      • Hormones
      • Growth factors

    Fibroblasts

    • Synthesises and secretes the fibrous proteins that make up the extracellular matrix except in bone and cartilage where this is done by the intrinsic cells.
    • Determine and define the local structure

    Collagen

    • Collagen is an important part of the connective tissue of the body that holds us together and provides both strength and flexibility
    • Production is within fibroblasts. It is the most abundant protein in the body comprises 25% of mammalian protein and has high tensile strength. Rich in proline and glycine.
    • Biochemically collagen consists of 4 long polypeptide alpha chains with rich amounts of glycine, hydroxyproline and hydroxylysine. Collagen may be broken down by Matrix metalloproteinases.
    • Collagen Synthesis is from Preprocollagen -> procollagen (composed of 3 polypeptide chains). Hydroxylation of proline and lysine in the Rough ER requires Vitamin C.
    • In Golgi aparatus procollagen peptidase removes non helical domains to form tropocollagen which then aggregates to form collagen fibrils. This forms a triple helix tensile strength.
    • Fibrillar forms have long stretches of triple helix. Non Fibrillar have interrupted or shorter helical structures.
    • Collagen types
      • Type I - Bone, tendon, dentin and skin. Provides tensile strength (Fibrillar)[Gene defect → osteogenesis imperfecta]
      • Type II - Hyaline and elastic cartilage (Fibrillar)
      • Type III - Reticular lamina of basement membrane and is formed initially during healing by reticular cells and then replaced by Type 1. Stains well with periodic-acid-Schiff (PAS) (Fibrillar)
      • Type IV - Found in the basal lamina and produced by epithelial cells (Non Fibrillar)
      • Type V - amnion and chorion in fetus (Fibrillar)
    • Collagen macroarchictecture
      • Some types form fibrils
      • Laid in a multidirectional form - e.g. skin
      • Laid in parallel layers - bone and cornea
      • Non fibrillar sheets - basement membrane Type IV
    • Disease
      • Defects in the enzymes to make collagen III e.g. procollagen peptidase and lysyl oxidase can produce the phenotype known as Ehlers-Danlos syndrome where there is decreased tensile strength and more tissue elasticity with cutaneous extensibility, bruising, and molluscoid pseudotumours.
      • Osteogenesis imperfecta patients have defects in Type I collagen.
      • Scurvy is caused by Vitamin C deficiency and affects collagen production. Vitamin C required for proline and lysine hydroxylation.

    Elastin

    • Small, thin and randomly coiled and branching fibres.
    • High proportion of glycine and proline amino acids which are non hydroxylated.
    • Fibrillin and glycoproteins and then elastin is deposited within the centres of the fibres
    • Progressive loss of elastin is important in ageing, emphysema and several diseases
    • Deficiency of fibrillin can lead to Marfan's syndrome

    Cartilage

    • Chondroblasts are derived from mesenchymal cells and contain glycogen and lipid and rough ER and golgi apparatus.
    • They are responsible for the production fo cartilage which consits of chroncytes and an extracellular matrix enveloped within perichondrium
    • Cartilage depends on diffusion through the ECM for its nutrients as it has not got a vascular supply.
    • Growth is by surface pericondrium based chrondroblasts differentiating and within by chondrocytes within the cartilage
    • Extracellular matrix is composed of
      • Type II collagen
      • Hylauronic acid
      • Glycosaminoglycans (chondroitin sulphate and keratan sulphate)
      • Chondroblasts become chondrocytes when locked into spaces called lacunae
    • There are three types of cartilage
      • Hyaline "greek - glass - like " cartilage
        • Lines the articular surfaces in synovial joints
        • Chrondrocytes within collagen and protein polysaccharide matrix
        • Reduces friction and shock absorbs
        • Seen prdominantly in the feus but becomes ossified by endochondral ossification
        • In adults forms articular surface of synovial joints, and is found in the nose, larynx, trachea and costal cartilages
        • Articular cartilage does not possess a perichondrium
      • Elastic cartilage
        • Similar structure to hyaline cartilage but also has embedded elastic fibres
        • Found in the ear, epiglottis and parts of the larynx
        • Regains its shaped after deformation
      • Fibrocartilage
        • High tensile strength and contains Type 1 collagen. Low water and GAG content. Lacks a perichondrium.
        • Found in areas such as tendons and ligaements insertiongs into bone as well as the tough fibrous part of intervertebral discs and pubic symphysis

    Synovial membrane

    • Lines the non-articulating surfaces
    • Folded increasing surface membrane
    • Produces synovial fluid
      • Clear, colourless, sterile, contains few cells
    • Intraarticular fibrocartilage
      • Chrondrocytes

    Bone

    Bone is a connective tissue which has an extracellular matrix which has become mineralised with calcium and phosphate conferring it incrreased rigidity and stength. It is highly vascular and metabolically active. It has various functions

    • Structure, support, protection of the body e.g. brain within skull
    • A rigid structure that allows movement and mobility
    • A store of calcium and phosphate
    • Contains haemopoietic cells

    Bone matrix

    • Organic 35%
      • Type I collagen
      • Proteoglycans - chodroitin sulpafate, keratan sulfate, hyaluronic acid
      • Osteocalcin
      • Osteopontin
      • Osteonectin
      • Bone sialoprotein
    • Inorganic 65%
      • Calcium phosphate
      • Hydroxyapatite

    There are basically two different forms see below

    • Compact /Cortical bone
      • Provides the outer smooth layer of bones. High strength and covers the inner spongy bone layer
      • Basic unit is the osteon which is dynamic and responsive to changing stress patterns
        • Periosteal blood vessels connect to the central vascular and lymphatic containing haversian canal which runs along the long axis of the bone by perforating volkmann's canals
        • Surrounding rings of lamellae form a calcified matrix embedded with osteocytes in lacunae with small finger like projections called canaliculi allowing communication between adjacent lacunae
        • Osteons are aligned along the lines of stress.
    • Trabecular or Spongy or Cancellous Bone
      • Honeycomb pattern to reduce mass. The basic unit is not the osteon.
      • Basic unit is an irregular lattice of trabeculae which may be filled by either red or yellow marrow.
      • Osteocytes exist within lacunae within trabeculae with the pattern of extending cancaliculi
      • Trabeculae are also aligned related to mechancial stress

      Macroarchictecture of Long bone

        • Shaft - diaphysis and ends - Epiphysis with Metaphysis in between
        • Growth plate between Metaphysis and Epiphysis
        • Periosteum coats bone except for articular surface and tendon/ligament insertion points. Contains osteoprogenitor cells
        • Hollow centre composed of marrow. Lined by endosteum.
        • Marrow cavity - contains red or yellow marrow

      Cells

      • Osteocytes
        • Usually found trapped within a lacunae but connect to other osteocyte by canaliculi separated by gap junctions
        • Manage bone turnover and maintenance
      • Osteoblasts
        • Control bone growth
          • produce the osteoid
          • mineralisation of osteoid
        • Secretes
          • Macrophage colony stimulating factor
          • Proteins
            • Type I collagen
            • Proteoglycans
            • Osteocalcin - needed to mineralise bone
            • Osteopontin
            • Osteonectin
            • Bone sialoprotein
            • Osteoprotogerin
            • RANKL - ligand for receptor for activation of nuclear factor kappa RANKL found in osteoclasts
        • Control
          • Alkaline phosphatase is found on surface of cell and hydroylses esters at alkaline pH
          • Vitamin D3 regulates osteocalcin which binds hydroxyapatite
          • Growth Hormone stimulates liver release of IGF1 which increases bone growth at epiphyseal growth plates
          • Parathormone binds to osteoblasts surface
      • Osteoclasts
        • Derived from monocyte-macrophage population

      Bone development

      Bone is usually created by the ossification of preexisting connective tissue. The mechanism below is essentially the same for the two types in that a trabecular network of spongy bone is laid down and then transformed into mature bone.

      • Endochondral ossification
        • A cartilage template is replaced by a bone matrix from chondroblasts which form chondrocytes. The cartilage model expands as the fetus grows by further division of the chondrocytes.
        • Growth continues but there is loss of chrondocyte and the lacunal spaces are formed.
        • Periosteal osteoprogenitor cells are carried deep by perforating vessels. They begin to deposit bone matrix.
        • The process of primary ossification progresses from the surface inwards forming the shaft (diaphysis) of the bone.
        • Secondary ossification
          • Occurs at the ends of the long bones at the epiphyses. This proceeds outwardly from the centre of ossification. The spongy bone remains on the interior.
          • This starts after birth. The growth plate separates primary (shaft) and secondary centres of ossification (bone ends) .
          • Eventually at a later stage the epiphyseal growth plate becomes replaced by bone and longitudinal growth stops.
      • Intramembranous ossification
        • Ossification of the mesenchyme the primitive connective tissue. Seen with the flat bones of the skull
        • Bone is laid down by osteoblasts laying own bone matrix without any preexisting cartilage formation
        • Calcium phosphate is deposited within the bone matrix and numerous centres of ossification coalesce

      Bone Structure

      • Periosteum and endosteum
        • Connective tissue layer that covers the bone externally (periosteum) or internal surface (endosteum) and contains osteogenic cells which can form osteoblasts allowing bone to expand in thickness and repair damage
      • Medullary "marrow" cavity
        • Lies in the centre of bones and contains either
          • Red marrow - produces red cells, white cells and platelets
          • Yellow marrow - fatty tissue and some connective tissue and may have some haemopoietic component. This is found more so with age as marrow spaces go from red to yellow due to reducing levels of erythropoietin.
      • Epiphysis
        • Function
          • Area of linear bone growth
          • No further expansion once epiphyseal fusion occurs
        • Structure
          • Bone
          • Calcified zone
          • Hypertrophic zone
          • Proliferative zone
          • Bone