The Patient - Musculoskeletal System

What are osteoblasts? bone makers (a mononucleate cell from which bone develops). What are osteoclasts? bone breakers (a large multinuclear cell associated with the resorption of bone). What are osteocytes? bone maintainers (mature bone cells that maintain the bone matrix) What is bone made of? calcium phosphate crystals (hydroxyapatite) in osteoid matrix (collagen and calcium). How is bone formed? Osteoblasts lay down osteoid (unmineralised bone tissue) to form outer surface of bone. Calcification - depositing of calcium phosphate crystals. Osteoblast becomes immobilised and then becomes osteocyte (which maintains surrounding osteoid). How are bones resorbed? This is the breakdown and assimilation of old bone and laying down new bone cells. Osteoclasts secrete acid and enzymes. Acid dissolves the calcium phosphate crystals and enzymes degrade osteoid. Calcium and phosphate are released into blood. How does a bone grow in width? Osteoblasts lay down new bone on outer surface. Osteoclasts resorb bone in inner surface of cavity. Minimises weight gain. 1/9 How do bones increase in length? Osteoblasts lay down new bone at epiphyseal plates. Chondrocytes produce new cartilage in epiphyseal plate, and this widens causing bone to lengthen. Cartilaginous epiphyseal plates are located near each end of the bone (between shafts of bone that are made of bone marrow and fat) and the secondary ossification centres with the epiphyses. Chondrocytes die and osteoblasts replace them, laying down bone. Epiphyseal plate closure happens at puberty (13-15 for girls, 15-17 for boys). It is affected by sex hormones and after this time, no further increase in length is possible. Dwarfism - decreased GH secretion in children Effects of abnormal growth hormone se- Gigantism - increased GH secretion in cretion children (pre-puberty) Acromegaly - increased GH secretion in adults (affecting visual characteristics) What other hormones (in addition to growth hormone) can affect growth? Thyroid hormones - required for synthesis of GH and needed for GH actions. Insulin - Needed for cellular actions (metabolism) of GH. Sex hormones - important for pubertal growth, actively promoting it. It is deficient postmenopausal. Glucocorticoids - inhibit growth. Children are treated with chronic doses of glucocorticoids in asthma, so inhaler devices are used to minimise exposure of glucocorticoids to the surfaces of lungs to avoid detrimental effects. What is osteomalacia (rickets)? Deficiency in bone mineralisation causing the softening and weakening of 2/9 bones. 3 in 100,000 per year are hospitalised because of this. What is osteomalacia caused by and how can it be treated? Caused by dietary insufficiency (Vitamin D2), lack of sunlight (Vitamin D3) and decreased calcitriol (caused by renal disease). It is treated with vitamin D - ergocalciferol (found in food) and calcitriol (if they have renal disease, it is an active form of vitamin D made in the kidney that activates vitamin D receptors). What is osteoporosis? Who is it more common in? Low bone density due to loss of hydroxyapatite, it is more common in post-menopausal women and those over 75 years. It can be glucocorticoid induced. Common fractures occur in the hip, forearm, spine and upper arm. With hip fractures, 25% tend to die within a year and What are the statistics for fractures due 50% lose some of their physical functo osteoporosis? tion. 33% of women over 50 will have a bone fracture related to osteoporosis and 300,000 patients have fragility fractures per year in UK. People are at risk of fragility fractures if they have previous personal/family history of fractures or falls, frequently use glucocorticoids, low BMI, smoking, drinking Who are more at risk of fragility fractures excessive alcohol or secondary causes due to osteoporosis? And how can it be (e.g. endocrine, GI or renal problems, reversed and improved? immobility). It can be reversed and improved with healthy diet, regular exercise, sunshine and vitamin D. What is the anatomy of the joint? The joint capsule surrounds the bone and is filled with synovial fluid which is associated with inflammation. The artic3/9 ular cartilage forms a covering at the end of each bone at the joint. What is osteoarthritis? Hard bony swelling of joints, mechanical stress wears down the cartilage and synovial fluid cannot provide protection. How can osteoarthritis be treated? Treat pain with topic and oral NSAIDs (aspirin, ibuprofen etc.), paracetamol, capsaicin (for knee joints) and opioids (for chronic pain), but exercise (muscle strengthening and aerobics), losing weight and joint surgery are other options. Most common cause of disability in the UK, 20.3 M suffer from joint pain, 4.5M What are the statistics for osteoarthritis, hand joints, 0.5M knee joints, 0.2M hip how many suffer from each joint pain? joints. Not all radiographic cases have pain. good prognosis, most cases of interphalangeal joint osteoarthritis (the two joints between the distal, medial and proximal What is the outcome of osteoarthritis if phalanges). Becomes asymptomatic afthe hand joints are affected? ter a few years and leaves patient with permanent swellings, thumb base may permanently lose function. What is the outcome of arthritis if the knee joint is affected? variable prognosis, third improve, third stay same, third worsen. Obesity can lead to poor outcome. often poor prognosis, some cases show What is the outcome of arthritis is the hip spontaneous improvement in symptoms joint is affected? and structure, but significant cases will need joint replacement within 1-5 years. Inflammation of the joint and synovial What is rheumatoid arthritis and how can membrane and damage to articular surit be treated? faces, autoimmune disease. Treat with steroids and TNF alpha antag4/9 onists, untreated leads to joint deformation. Deposition of uric acid crystals (found in red meat and alcohol for example) in joints. Often affects big toe and triggers What is gout? Who is more affected and acute arthritic symptoms due to inflamhow is it treated? matory response. Age is a massive risk factor and affects men more. Usually treated with NSAIDs. What are muscles? Muscles are a group of fascicles and muscle fibres extend length of muscle from tendon to tendon. Muscle --> fascicle --> muscle fibre --> myofibril --> sarcomeres --> myosin (thick) and actin (thin) Myofibrils are what give skeletal muscle a striated appearance. The myosin and What makes skeletal muscle striated? actin filaments give these striations and form sarcomeres. What is the thin filament made of? - Actin - Troponin - Tropomyosin What is actin? globular multifunctional contractile protein containing myosin binding sites. Two F actin strands form the double helix. regulatory proteins which bind to tropomyosin and calcium to regulate skeletal muscle contraction. What is troponin? Troponin holds tropomyosin over myosin binding sites on actin (muscle relaxed). When calcium ions bind to troponin, tro5/9 ponin moves the tropomyosin to reveal binding sites for myosin so that muscle can contract. What is tropomyosin? It is a long, fibrous protein that winds around the actin polymer, blocking all the myosin-binding sites. It regulates muscle contraction and relaxation. What is the thick filament? Myosin has two binding sites, one for actin and one for ATPase (nucleotide binding site) Myosin tails face the M line whilst heads face thin filaments. What makes up the sarcomere? - Dark band (overlapping myosin and actin) - Light band (only actin) Z line (edges of the sarcomere, made of actin) M line (middle of sarcomere) H zone (zone in the middle where only myosin is present) What happens to the sarcomere when muscle contracts? - Light band shortens. - H zone shortens. - Dark band remains the same length. How does the muscle generate force through the cross-bridge cycle? Calcium ion channels open due to action potential and diffuse into sarcolemma. They bind to troponin and causes tropomyosin to move allowing myosin to bind to actin and form a cross-bridge. Actin gets pulled to middle of sarcomere, a power stroke. ADP and inorganic phosphate are released from myosin head. A new ATP molecule attaches to myosin which causes myosin to detach from actin and the ATP is hydrolysed. Myosin attaches to another binding site. 6/9 How muscle contractions are turned on and off. This is when an action potential in the sarcolemma causes contraction. It What is excitation-contraction coupling? requires calcium release from sarcoplasmic reticulum and is dependent on neural input from motor neuron at the neuromuscular junction. Neurotransmitter is released at neuromuscular junction, causing an action potential in the sarcolemma of the muscle fibre and down the transverse tubules. What is the process of excitation-con- DHP (dihydropyridine) receptors of the T traction coupling? tubules open calcium ion channels in the lateral sacs of the sarcoplasmic reticulum. Calcium increases in cytosol, bind to troponin and cross-bridge cycling occurs. How is contraction terminated? Calcium must leave troponin so that tropomyosin can cover the binding sites on actin. Calcium ion ATPase in sarcoplasmic reticulum transports calcium from the cytosol back into the reticulum. Acetylcholine stops being released into the synapse. ATP is used by muscle for the cycle and is split by myosin ATPase. Binding of ATP Why is ATP needed for muscle contrac- to myosin causes dissociation. It is also used for transport of calcium back into tion? sarcoplasmic reticulum. It maintains ion gradients and membrane potential. How is ATP produced? Anaerobic glycolysis produces 2 ATP, oxidative phosphorylation in mitochondria produces 32 ATP, and phosphorylation of ADP to ATP by creatine phosphate is instantly available but limited to 5 ATP. 7/9 What is oxidative phosphorylation? Oxidative phosphorylation is the primary energy source when oxygen supply is adequate during light/moderate exercise. It increases ventilation, heart rate, contraction and dilates vessels to muscle. Muscle stores have limited amount of glucose as glycogen, so glucose and fatty acids are delivered to muscle cells by blood after 30 minutes. When oxygen supply to muscle is limited (like during intense exercise), anaerobic How is ATP obtained when there is limitglycolysis is the primary source of ATP, ed oxygen? but only 2 ATP per glucose and there is a build-up of lactic acid. What is motor neurone disease? Selective degeneration of motor neurons and skeletal muscle fibres. Results in skeletal muscle paralysis, there is therapy to slow down the disease progression but no definite treatment. Autoimmune disease where patients develop antibodies against acetylcholine receptors. This prevents acetylcholine binding to the receptors at the neuromuscular junction, this means muscles will What is myasthenia gravis? What are the not contract. symptoms and how can it be treated? It causes muscle weakness (like poor eye control) and is treated by targeting antibodies to prevent their production. Acetylcholinesterase can be inhibited too to stop them from breaking down acetylcholine. An X linked inherited disorder which mainly affects men. What is Duchenne Muscular Dystrophy? Causes muscle weakness due to abnorWhat are the symptoms and how can it mal muscle proteins (defective). be treated? Difficult to treat but can use gene therapy to transfect the muscle fibre with a con8/9 struct that correct the genetic defect (to produce normal muscle proteins). What is polymyalgia rheumatica? How do you treat it? Inflammatory condition affecting numerous skeletal muscles, particularly the shoulder and thighs. Can be associated with flu symptoms, mostly seen in those above 60 with 2/3 being female. Treated with corticosteroid anti-inflammatory treatment (oral prednisolone). What is fibromyalgia? What are the symptoms? Affects 4% of population and is difficult to diagnose. Symptoms include widespread musculoskeletal pain (made worse by sustained activity), tiredness/lack of energy, sleep disorders and headaches. Not an effective therapy to treat it yet. What is the anatomy of smooth muscle? Spindle-shaped, small, no striations. What makes cardiac muscle similar to skeletal muscle? - Striated - Regulated by troponin and tropomyosin - Has T tubules and sarcoplasmic reticulum - similar to slow oxidative fibres: myoglobin, mitochondria, slow to fatigue What makes cardiac muscle similar to smooth muscle? - It has gap junctions with intercalated discs - It has pacemaker cells (controlling frequency of contraction) - Innervated by the ANS - Influenced by hormones and paracrines - Calcium comes from ECF and sarcoplasmic reticulum 9/9