Overview

Question 1

Describe the statistics of arthritis

Answer 1

• Leading cause of chronic pain
• High multi-morbidity
• 28% GP consultations
• 16,000 children have juvenile idiopathic arthritis
• Increase over next 2 decades because ageing obese population

Question 2

How does long bone develop?

Answer 2

• Bone forms as cartilage first
• Blood vessels invade cartilage
• Osteogenic cells invade with blood vessels
• Cartilage remains in growth plate
• Adult bone

Question 3

Describe the juvenile growth plate

Answer 3

-Epiphysis
=cavity, cartilage, synovium, joint capsule, bone, epiphyseal vessels
-Physis or growth plate
=Resting, dividing, proliferating, dying, bone formation (hypertrophic, resting, proliferative)
-Metaphysis
-Diaphysis
=Nutrient vessels, periosteal vessels

Question 4

What are the types of connective tissues?

Answer 4

• Connective tissue proper= loose (fibers create loose open framework, areolar, adipose, reticular) dense (fibers densely packed, dense regular= tendons, ligaments, dense irregular=capsules and elastic)
• Fluid connective tissues= blood (contained in c.v. system), lymph (contained in lymphatic system)
• Supporting connective tissues= cartilage (hyaline, fibrocartilage, elastic= load-bearing, resilient matrix/ rubbery), bone (solid, crystalline matrix, cancellous, compact)

Question 5

What are the 4 basic groups of tissues in the body?

Answer 5

• Epithelia= cover surfaces, glandular elements
• Neural
• Muscular
• Connective tissues (50% body weight)

Question 6

Where does connective tissue come from?

Answer 6

• Develop from the mesenchymal component of embryonic mesoderm and are heterogenous in nature with differing functional properties
• Consist of widely separated cells situated in an extracellular matrix (ECM) the main component of the tissue which is made of extracellular fibres, a ‘ground substance’ and interstitial fluid
• ECM synthesised and secreted by cells (adipose tissue where cells are very close together and blood and lymph where the fluid in which cells are suspended is not secreted by cells are exceptions)

Question 7

What are the components of connective tissues?

Answer 7

• Cells- ‘resident’ = fibroblasts, chondrocytes, bone cells
• Extracellular matrix- fibrillar proteins (collagens), ‘ground substance’ (proteoglycans, PGs comprise one or more glycosaminoglycans/ GAGs- aggrecan- the main cartilage PG; resist compressive forces)
• Interstitial fluid- complex ionic and osmotic composition because of fixed negative charges on GAGs

Question 8

What are ‘immigrant’ cells?

Answer 8

• Macrophages which can be stationary (attached to the fibres of the matrix)/ motile
• Large cells derived from hemopoietic stem cells of the bone marrow, circulate in the blood as monocytes, enter tissues to become macrophages
• Phagocytose bacteria, dead cells and cellular remains

Question 9

Describe lymphocytes

Answer 9

• Normally present in low numbers and are mostly of the small variety with a round nucleus
• There are two types; B lymphocytes concerned with humoral immunity and T lymphocytes involved in cellular immunity

Question 10

Describe neutrophils

Answer 10

• Considerable phagocytic ability

- Numbers normally low, rise following infection

Question 11

Describe mast cells

Answer 11

• Develop in the bone marrow from the hemopoietic stem cell and following maturation enter the tissues
• They are round cells with a small nucleus and relatively little rough surfaced endoplasmic reticulum
• Prominent Golgi apparatus and a large number of granules in their cytoplasm which contain heparin, histamine and lysosomal enzymes.
• They are involved in inflammation and in hypersensitivity states.

Question 12

What are the two types of resident cells?

Answer 12

Fibroblasts

Chondrocytes

Question 13

Describe the morphology of resident cells

Answer 13

F: Flat, spindle-shaped, irregular border, cell processes (often branching)
C: v. low density; morphology variable – depends on depth in cartilage (flat at surface, rounded in deep zones)

Question 14

Describe the cytoplasmic contents of resident cells?

Answer 14

F: Large nucleus, a nucleolus, well developed RER & Golgi apparatus, many mitochondria & secretory vesicle
C: Much RER & well developed Golgi. Cytoplasmic glycogen, lipid

Question 15

Describe the function of resident cells

Answer 15

F: Active synthesis & secretion of ECM components; some degradative enzymes
C: Active synthesis, secretion & turnover of ECM components; some degradative enzymes

Question 16

Describe the products of synthesis of resident cells

Answer 16

F: Synthesis & secretion of collagen (mainly Type I), elastin & fibrillin and other fibres, & PGs (small Mol. Wt. types)
C: Synthesis & secretion of collagen (mainly Type II) & PGs (aggrecan); also degradative enzymes1 and their inhibitors2 (MMPs and TIMPs)

Question 17

What are the 4 major proteins that form fibrils in the ECM?

Answer 17

• Collagen= rope-like, determines the tensile properties of a connective tissue
• Elastin= determines elasticity of connective tissue
• Fibrillin= forms microfibrils that act as scaffold for elastin
• Fibronectin= act as attachment points for anchoring of cells in the tissue (also binds to collagen and PGs)
• Other extracellular proteins; in bone, osteopontin binds to cells and also bone mineral and may play a role in anchoring osteoclasts to mineral surface, also osteonectin, osteocalcin

Question 18

What is Marfan’s syndrome?

Answer 18

• Genetic disorder of connective tissue
• 70-80% familial, autosomal dominant inheritance
• Mutations in gene coding for fibrillin, on chromosome 15
• Changes in this gene lead to changes in connective tissues especially those of the skeleton, eyes (lens dislocated) and cardiovascular system (in heart, mitral valve prolapse)

Question 19

Why is repair of connective tissue so poor/ non-existent?

Answer 19

• Poor vascular supply
• Limited supply of nutrients
• Very low synthesis rates of some tissue components
• Loss of cell-matrix interactions- leads to irreversible loss of phenotype
• Integration of repair tissue very poor
• Mechanical properties of repair tissue inferior/ weak

Question 20

What is the bony skeleton affected by?

Answer 20

1. Mechanical stress of physical activity (strength and shape of bone is remodelled to take account of prevailing level of mechanical stress)
2. The sex of the individual
3. The diet= vitamins A, D, C, calcium, phosphate and protein
4. Hormones (PTH, calcitonin, 1,25(OH)2D3, growth hormone, T3 & T4, oestrogens, androgens, glucocorticoids
5. Age- with advancing age, bone resorption exceeds deposition, effect greater in females than males

Question 21

What is osteoporosis?

Answer 21

Condition of increased bone fragility due to low lone mass i.e. decreased mass of bone per unit volume; the porosity of the skeleton is increased= the risk of fractures is increased
-Bone resorption greater than deposition

Question 22

What are the primary causes of osteoporosis?

Answer 22

• Effects of ageing; a loss of 0.7% of bone/year is normal. With increased age, bone remodelling is not so efficient; bone resorption>deposition (osteoblasts less efficient).
• Growth factors are not so powerful. The elderly are less mobile - leads to increased bone loss.
• Decreased renal function to decreased 1,25 (OH)2 D3 → decreased Ca2+ absorption → decreased plasma Ca2+ level → increased PTH → increased bone resorption.
• Post-menopausal; In females in the first 10yrs post-menopause, ~2% of the cortical bone and 9% of cancellous (spongy) bone is lost/yr. With loss of oestrogen there is increased secretion of interleukin-1 by monocytes resulting in increased osteoclast recruitment and activity. Bone is reabsorbed. There is increased osteoblast activity but this doesn’t compensate for the bone loss.

Question 23

What are the secondary causes of osteoporosis?

Answer 23

• Associated with other causes; Endocrine (hyperthyroidism, Acromegaly, Cushing’s syndrome, Diabetes mellitus type 1), Malnutrition incl. Vitamin C deficiency; drugs (glucocorticoids, chemotherapy) miscellaneous (e.g. prolonged immobilisation).
• With endocrine causes, there is decreased protein synthesis which is essential for collagen formation and the osteoblasts are less active. A similar effect occurs with the drugs above.
• Vit. C deficiency leads to decreased collagen formation. With prolonged immobilisation there is decreased osteoblastic activity for bones thrive on mechanical stress (mechano-transduction plays a key role in this process). Bone re-absorption exceeds deposition.
• Clinically, patients with OP may have fractures; those of the femoral neck and wrist are most common. In the case of the vertebral column, with increased osteoclast activity in the cancellous area of the vertebral bodies, the trabeculae are thinned, resulting in fractures. Those of the thoracic and lumbar regions are painful.
• If there are multiple fractures in the vertebral column, a deformity of the spine may occur (a hump – kyphosis an abnormally convex curvature) and also loss of height.
• This differs from scoliosis which is an idiopathic condition leading to a sideways curve of the spine, due to a combination of genetic and environmental factors.

Question 24

What is osteoarthritis?

Answer 24

• Most common degenerative joint disorder.
• Causes cartilage failure, reduction of mechanical resilience of cartilage, depletion and loss of the ECM until bone rubs on bone and the joint is un-usable.
• More accurate to describe as osteoarthrosis because in its primary form it is not inflammatory (it is means inflammatory).
• Better described as disorder/ syndrome rather than disease, since probably arises from several interacting factors (i.e. is multifactorial), not single cause

Question 25

What are the causes of osteoarthritis?

Answer 25

- In primary form, which is the majority of cases of OA, it appears insidiously when a person is aged in the 50s probably as part of the ageing process; usually only one joint is affected. By 65yrs, ~85% of people have evidence of OA but only ~25% have the symptoms. - In males, the hip joint is commonly affected, in the female the disorder involves the knees and joints of the hand (proximal and distal inter-phalangeal joints); at the distal interphalangeal joint (especially in females) Heberden’s nodes (osteophytes, calcific spurs) may be seen. - OA is more generalised and more severe in older women. OA hips more frequent in Caucasians. In some cases, OA appears earlier in life as a result of a pre-disposing cause (secondary OA) e.g. joint trauma, congenital abnormality of joint, or obesity placing increased stress on joints

Question 26

Describe the progressive destruction of the articular cartilage of the joint in OA

Answer 26

- Fibrillation (splitting) of the cartilage occurs, beginning as surface roughening often in non-weight-bearing area of the joint surface. - The hydration (water content) of the interstitial fluid of the ECM increases and PG concentration decreases. (Note this differs from aged cartilage since cartilage hydration decreases with age). - There is a weakening to the collagen meshwork allowing increased uptake of water by the proteoglycans and the collagen fibrils are pushed further apart. - As the cartilage breakdown progresses the areas involved are larger and deeper zones of the cartilage are affected. - In parallel, the weight-bearing areas start to degenerate. - Initially fibrillation is tangential, but later the split lines are vertical. - Chondrocyte cell death occurs, but some chondrocytes proliferate into cell clusters. - Ultimately, full thickness portions of the articular cartilage are broken off, and enter the joint as loose bodies (‘joint mice’) which can cause further joint damage. - The sub-chondral bone plate is exposed, and the resulting friction smoothes and polishes the exposed bone (bone eburnation) which can be exceedingly painful. - At this time, thickening of the sub-chondral bone plate and the underlying cancellous bone also occurs. Bony outgrowths (osteophytes) occur at the edges of the articular surface which can be seen on plain x-ray images

Question 27

Describe how synovial membrane is affected in OA

Answer 27

The synovial membrane is much less affected compared to the articular cartilage, but in later stages shows some vascular congestion and there are areas of inflammatory changes and fibrosis

Question 28

Describe the mechanisms underlying the initiation and progressive changes in OA

Answer 28

(a) normal load on abnormal cartilage (resulting from inflammation, metabolic and genetic diseases, ageing, toxins and toxic metabolites) (b) abnormal load on normal cartilage (with obesity, anatomical abnormalities, subchondral and gross remodelling of bone, loss of stability, trauma causing abnormal load). - chondrocyte loss and/or changes to matrix metabolism can start a ‘vicious cycle’ leading to PG loss and damage to the collagen meshwork

Question 29

What is Rheumatoid arthritis?

Answer 29

- Chronic inflammatory condition which predominantly affects joints resulting in synovitis (inflammation of the synovial membrane) which can lead to destruction of the articular cartilage and ankylosis1 of the affected joint. - However, there are also systematic effects, for other joints such as skin and blood vessels can be affected in the condition. It has been estimated that 1% of the world’s population are affected by RA, and is 3x more common in females than males. RA most often makes its appearance in the 3rd to the 5th decades. It is the most common inflammatory disease of joints

Question 30

Describe the pathophysiology of RA

Answer 30

- In the affected joints, the synovium is swollen (oedematous) and its vascularity is increased. - The stroma of the synovium is filled with lymphoid follicles, plasma cells and macrophages. - Instead of the synovial surface being smooth it is covered with frond-like processes and parts are covered by fibrin. - The synovial fluid volume is increased, it is turbid and the fluid contains neutrophils. The inflamed synovium gradually creeps over the articular cartilage (forming a pannus); erosion of the underlying cartilage occurs. - Cytokines and other mediators released by the synovial and inflammatory cells cause erosion of the cartilage and also activation of osteoclasts leading to the erosion of bone. - When the articular cartilage on the two bone ends has been completely eroded, the pannus fills the space between the two bones; a fibrous and then a bony ankylosis occurs. - The inflammation can also cause damage to ligaments and muscles around the joint

Question 31

Describe the aetiology of RA

Answer 31

- Not known for certain, but may involve a genetic susceptibility or an autoimmune reaction. - Certain individuals may have a genetic disposition to RA, for it has been found that 65-80% of people developing RA have HLA antigens DR1 or DR4. - The alleles associated with a susceptibility to RA have a common area of 7 amino acids (AA 67-74) located in the antigen binding area of the DR molecule close to the T cell recognition site. This may be the binding site of a molecule setting in motion the train of events leading to the synovitis. - Exogenous or auto-immune antigenic peptides might bind to this area leading to T lymphocyte activation and the initiation of the disease. - The Epstein Barr virus glycoprotein contains the same amino acid sequence as the above epitope. With respect to an auto-immune reaction, type II collagen of the Fc portion of IgG may also bind to this site. - When the T lymphocytes are activated, this leads to activation of B lymphocytes and antibody production

Question 32

What is ankylosis?

Answer 32

- In RA, the inflamed synovial membrane can thicken into a pannus which is abnormal tissue that attaches to the articular cartilage. - The pannus secretes degradative enzymes and erodes the cartilage and sometimes the underlying bone) and eventually scar tissue forms can connects the bone ends. - Later this scar tissue ossifies and the bone ends fuse together immobilising the joint. This end condition (termed ankylosis) often produces bent deformed fingers - not all cases of RA progress to this severely crippling stage, but all cases do involve restriction of joint movement and extreme pain).