MSK and Rheumatology

What is the MSK system?

the anatomical structures that allow locomotion

How many bones in an adult vs child?

• 206 bones in adults

• 270 in children

What are components of the MSK system?

• bones

• joints → where two bones meet

• cartilage → strong connective tissue that prevents joints rubbing together

• muscles

• tendons → connective tissue attaching muscle to bone

• ligaments → connective tissue connecting bones

What are the 2 components to the skeleton?

• Appendicular- pectoral girdle, upper and lower limbs, pelvic girdle

• Axial- cranium, vertebral column, rib cage

What are the functions of the skeleton? (5)

1. rigidity/support- helps you stand up

2. protecting vital organs (skull, rib)

3. movement- works with muscles for this

4. mineral storage/homeostasis (regulation of calcium and phosphate)

5. bone marrow produces blood cells

What cells are in bone?

• osteogenic cell

• osteoblast

• osteoclast

• osteocyte

what do osteogenic cells do and where are they found?

• bone stem cell

• deep layers of periosteum

what do osteoblasts do and where are they found?

• bone building cells that secrete osteoid and catalyse osteoid mineralisation

• growing portions of bone including periosteum and endosteum

what do osteoclasts do and where are they found?

• bone consuming cells that dissolve and reabsorb bone by phagocytosis

• bone surfaces at the site of old, injured and unneeded bone

what do osteocytes do and where are they found?

• mature bone cells that are formed when osteoblasts become embedded in their owns secretions

• sense mechanical strain to direct osteoclast and osteoblast activity

• entrapped in matrix

Describe bone composition

• cells

• ECM → organic component (osteoid) and inorganic component (minerals)

Why is the balance of osteoblast vs osteoclast activity important?

More osteoclast activity than osteoblast then lower bone mineral density

What drugs can we use to treat osteoporosis?

• drugs that inhibit osteoclast activity

• drugs that increase osteoblastic activity

Drugs that inhibit osteoclastic activity:

• bisphosphinates → slow down bone reabsorption

• denosumab

drugs that promote osteoblastic activity

• teriparatide

• romosozumab

How do we measure bone mineral density?

Dual Energy X-ray Absorpitometry Scan (DEXA scan)

Where is bone mineral density measured?

hip and lumbar spine (L)

What metrics are used to report bone mineral density (BMD)?

• T SCORE: standard deviations from the average mean for healthy young adults of the same sex (matters more)

• Z SCORE: standard deviations from the mean for age-matched adult of the same sex

  T score	Interpretation
  >-1	“normal”
  <-1 and > -2.5	osteopenia - thinner BMD but not osteoporosis yet
  <-2.5	osteoporosis

What are bones the body’s primary store of?

Calcium

What are 2 key hormones that affect bone and regulate calcium metabolism?

Vitamin D and PTH

What are the two types of vitamin D?

Vitamin D2 - ergocalciferol

Vitamin D3 - cholecalciferol

source of vitamin D2

Diet (plants) e.g. UV-exposed mushrooms, fortified cereals

source of vitamin D3

• Sunlight

• Diet → animal sources - fatty fish, egg yolks, liver

Where is vitamin D hydroxylated as part 1 of the 2 step activation?

Liver to 25-hydroxy vitamin D

Where does vitamin D get converted into its bioactive form?

Kidney to 1,25-dihydroxyvitamin D (calcitriol)

What are the results of the bioactive form of vitamin D being in the body?

• increases Ca2+ absorption

• decreases renal Ca2+ excretion into urine

• increases bone mineralisation

• increases osteoblast activity

How would you treat vitamin D deficiency/insufficiency?

• prefer to give vitamin D3

• has longer half life

What is vitamin D deficiency?

• inadequate bone mineralisation

• accumulation of unmineralised matrix (osteoid)

How does vitamin D deficiency present in adults?

osteomalacia (softening of bones)

How does vitamin D deficiency present in children?

rickets (deformed bones) → skeletons still developing

What are the risk factors of vitamin D deficiency?

• lack of sun exposure

• poor diet

• malabsorption

• liver and renal diseases so inadequate hydroxylation to form bioactive vitamin D

How would you treat end-stage kidney disease?

• 1-OH vitamin D

  • kidneys cannot convert 25-OH vitamin D to 1,25-dihydroxy vitamin D (active form), because they are not working

What is PTH?

Parathyroid hormone

• released from the parathyroid glands - 4 of them posterior to the thyroid

What is the role of PTH?

• stimulates osteoclasts → bone resorption → releases ca2+ and phosphate into blood

• increased renal resorption of calcium so theres less calcium in the urine

• decreased resorption of phosphate, so increased phosphate in the urine

• increased renal production of active 1,25(OH) vit D

  • this indirectly increases calcium ion intestinal absorption

What is PTH’s net effect on serum levels?

Increases calcium ion levels, decreases phosphate levels

What is the clinical significance of PTH?

• hyperparathyroidism ( increased PTH levels)

• hypoparathyroidism (decreased PTH levels)

What is primary hyperparathyroidism?

• usually asymptomatic

• mildly increased calcium ion

• osteoporosis / fragility fractures risk due to bone resorption

• bone resorption - “brown tumours”in bone, pepper pot skull

• may have symptoms of hypercalcemia “bones, stones, psychic moans (depression), abdominal groans”

What are the tests for hyperparathyroidism?

increased calcium ion levels, increased PTH (not too high)

What are the causes of hyperparathyroidism?

benign solitary adenoma of the PT gland

What is secondary hyperparathyroidism?

appropriate response (increased PTH) to decreased calcium ion levels due to low vitamin D

What are the tests for secondary parathyroidism?

decreases calcium ion levels, appropriately increased PTH levels

What is tertiary hyperparathyroidism?

after prolonged period of secondary hyperparathyroidism:

• glands become hyperplastic

• glands autonomously produce excess PTH

• loss of normal feedback loops

• seen in End stage kidney disease

What are the tests for tertiary hyperparathyroidism?

• increased calcium ion, inappropriately excess PTH

What is malignant hyperparathyroidism?

secretion of PTrP (parathyroid-related protein) by a tumour

• usually lung squamous tissue carcinoma

• this mimics effect of PTH

what are the tests for malignant hyperparathyroidism?

increase calcium ion levels, decreased PTH levels

• the assay test does not pick up PTrP

3 mechanisms of bone fractures:

• trauma → high energy / low energy

• stress → abnormal stress on the bone

• pathological → normal stress on the bone

Example of traumatic fractures

• Falls

• Road traffic accident (RTA)

• Assault

• Sports

• Crush injury

Define a joint

A point at which 2 bones meet

What are the 3 types of joints - structural classification?

• fibrous joints → no space between joints → no movement

• cartilaginous joints → bones connected by cartilage → very limited movement

• synovial joints → space between adjoining bones called synovial cavity filled with synovial fluid

what are the 3 types of joints - functional classification?

• synarthroses: generally allow no movement

• amphiarthroses: allow very limited movement

• diarthroses: allow for free movement of joint

What are examples of fibrous joints?

• sutures - immovable, found between bones of skull

• syndesmosis eg. between tibia and fibula

• interosseous membrane - dense connective tissue connecting two long adjacent long bones

What are the functional types of synovial joints?

1. Hinge (knee) → monoplanar

2. Ball and socket (shoulder and hip) → multiplanar

3. Pivot joint (cervical spine) → allow limited rotating movements

4. Condyloid (AKA Ellipsoidal joints) (wrist) → allow all types of movement except pivotal movements

What is the structure of a synovial joint?

• articular cartilage → made out of 2 different collagen types - type II and aggrecan

• synovium → tissue that contains macrophage and phagocytic cells

• synovial fluid → is hyaluronic rich fluid (lubrication)

How are synovial joints stabilised?

• Bone surface congruity (how well 2 bones in joint align) is quite stable

• muscles have tendons that join bone to stabilise it

What are ligaments?

• strong soft tissue structures - connective tissues made up of type I collagen which stop bones moving in excess extreme directions (restrict joint motion)

• less blood supply than muscles

• connect bone to bone

• stability and proprioception

How are ligaments stabilised?

• More and tighter ligaments means more stability but less mobility and vice versa

• Poor stability increases risk of dislocation- articular surfaces move out of alignment

What are tendons?

• connect muscle to bone (strong soft tissue structures) made up of type I collagen

• less blood supply than muscles

• transmit forces

• comprised of collagen fibrils arranged into fibres

tendiopathy definition

• chronic

• neovascvularisation (growth of new blood vessels) + disordered collagen fibres

What is the function of cartilage?

provides a smooth lining at a joint to allow the ends of two bones to meet with minimal friction

What is cartilage composed of?

1. specialised cells eg. chondrocytes

2. extracellular matrix: water, collagen and proteoglycans (mostly aggrecan)

What is the blood supply to cartilage?

It has no blood supply - it is avascular, why it can be dangerous to injure as it cannot heal

What is aggrecan?

• proteoglycan

• has many chondroitin sulphate and keratin sulphate chains (essential to attract water retention)

• characterised by its ability to interact with hyaluronan (HA) to form large proteoglycan aggregates (essential for strength to withstand compression)

What is arthritis?

disease of the joints (2 broad divisions - osteoarthritis and arthritis associated with inflammation)

What is osteoarthritis?

generative arthritis where there is a loss of cartilage (generally considered non-inflammatory)

What are the arthritis diseases associated with inflammation?

Autoimmune

• rheumatoid arthritis → immune system attacks itself

Septic arthiritis

• bacterial infection to the joint

Crystal Arthiritis

• gout and pseudogout → crystals trigger inflammation

What are the functions of muscles?

• force generators of the MSK system

• move bones around a joint

• protect underlying structures

What are examples of where muscles move a joint?

A hinge joint

• muscles paired as agonist or antagonists

• for example, the bicep and tricep pair one contracts other relaxes

How do muscles respond to increased load?

hypertrophy → increase their size

How do muscles respond to disuse?

atrophy (especially in joint disease)

What are the 4 layers of hyaline (articular) cartilage?

1. superficial - flatter chondrocytes parallel to hyaline cartilage surface

2. intermediate - chondrocytes more widely spaced

3. deep - chondrocytes stacked and lots of proteoglycan

4. calcified - attachment to bone after tide mark

What is the role of a chondrocyte?

• the only cell in articular cartilage

• produces and degrades cartilage extracellular matrix

• interacts with ECM and GFs, mechano-transduction

• highly metabolically active

• No cell division after adolescence (IMPORTANT)

• Exists in relative hypoxia so reliant on nutrients from synovial fluid diffused through bone

What makes up the ECM of healthy cartilage?

• aggrecan → exert swelling pressure, resists compression

• type II collagen, high tensile strength

• water

What is the main purpose of Type II collagen in cartilage?

to provide high tensile strength

What is a distinct property of chondrocytes?

they exist in relative hypoxia as no nerves or vasculature surrounds them

What enzyme breaks down collagen and where along the chain does this occur?

• collagenases e.g MMP-1, MMP-8, MMP-13, metalloproteinases these are very good and abundant in disease

• common one is MMP-3 a stromelsyin

• clips 3/4 of the way through the collagen chain (between N and C terminals)

Which collagenase is non-specific?

Cathepsin K

NB inhibitor of this can be used as treatment of OA

What is the structure of aggrecan?

• G1, G2, G3 main globulin structures

• glycosylated chains (carbohydrate chains) of chondroitin sulfate and keratin sulfate

• G1 interacts with hyaluronan all forms aggregates

Which 2 enzymes break down aggrecan and where on aggrecan does this occur?

1. matrix metalloproteinases e.g MMP-3

2. aggrecanases e.g ADAMTS-4&5

• between G1 and G2 component of aggrecan

What are the consequences of aggrecan breakdown?

• leads to loss of the negatively charged element of aggrecan (point from G2 after lost)

• reduced ability to hold water

Why does matrix loss occur?

due to an imbalance between excessive degradation of ECM and reduced anabolism

How does cartilage maintain its thickness?

requires a mechanical load which is different depending on whether you are:

• walking

• jumping

• running

• climbing stairs

What are the molecular changes in cartilage in OA? (3)

1. proteoglycan (aggrecan) fragmented by excessive aggrecanases

2. collagen is broken down by collagenases (irreversible as not enough type II made)

3. less water in matrix → initial swelling is lost

What are the progressive changes to cartilage in OA? (4)

1. loss of proteoglycans in superficial zone

2. fibrillation - loss of articular cartilage integrity

More established-

1. fissuring - crack in cartilage

2. partial/full thickness loss , osteophytes (new bits of bone forming), bone cysts and synovial inflammation

Is the onset gradual or rapid for OA?

gradual

How is OA diagnosed clinically? (5)

1. joint pain typically on activity

2. stiffness <30 mins

3. loss of function

4. X-ray

What are the main features seen on an x-ray of a patient with OA? (3)

• joint space narrowing leads to bone on bone contact

• osteophytes (bone spurs) and bone cysts

• subchondral sclerosis (thickening of bone increased whiteness)

When might blood tests be used in the diagnosis of OA?

• low inflammatory response e.g slight increase in CRP or normal levels

• To make sure tests for rheumatoid arthritis are negative

• tests for iron, calcium, glucose, PTH to exclude secondary causes

Which other tissues apart from articular cartilage are also affected in OA?

1. ligament and soft tissue

2. synovial

3. subchondral

How can OA be managed according to NICE guidelines?

1. exercise

2. weight management

3. information & support e.g reinforcing idea that OA is not inevitable

4. anti-inflammatory drugs for pain relief, usually gel

What are the surgical options for OA?

1. arthroplasty (total joint replacement e.g. hip/knee

2. uni-compartmental replacement (replacing only one side of knee or hip)

3. trapeziectomy (removal of thumb bone) for base of thumb OA

What are the 3 types of muscle?

1. smooth muscle → under involuntary control from ANS

2. cardiac muscle → under involuntary control from ANS

3. skeletal muscle → under voluntary control from somatic nervous system

What are the different arrangements of muscle fibres? (6)

1. triangular

2. unipennate

3. bipennate

4. multipennate

5. fusiform

6. parallel

How is skeletal muscle arranged from a macroscopic to microscopic level?

muscle → bundles of fascicles → myofibre → myofibril → myofilaments

What is the structure of a myofibre?

• Covered by sarcolemma (plasma membrane)

• Transverse - tubules (T-tubules) tunnel into centre

• Cytoplasm in the fibres is sarcoplasm - myoglobin and mitochondria are present

• Sarcoplasmic reticulum - network of fluid filled tubules

• Composed of myofibrils

Which 2 types of protein make up myofibrils?

1. myosin

2. actin

What is the structure of a myofilament?

Light and dark bands give muscle striated (striped) appearance

Does not extend along length of myofibres

Myosin and actin overlap and are arranged in compartments called sarcomeres

Describe the bands in a myofilament

• dense protein - z-discs separate sarcomeres actin comes out of either end of here

• dark bands - A band is thick myosin and actin overlap

• light bands - I band is thin actin filament only

• H zone is myosin only

• M line is middle of a sarcomere where myosin comes out of

Describe the structure of myosin.

• 2 globular heads

• single tail formed by 2 alpha helices

Describe the structure of actin.

• actin molecule twisted into a helix

• each molecule has a myosin binding site

• tropomyosin wrapped around actin

• troponin complex sits on tropomyosin

What is the role of the troponin complex?

• Ca2+ binds to it

• causes tropomyosin to move and uncover myosin binding sites