| A | B |
|---|
| rickets | expansion of the zone of hypertrophied chondrocytes |
| Fibronectin | Relatively abundant, may help regulate osteoblast differentiation |
| Osteonectin | "Bone connector" may regulate mineralization |
| Thrombospondin | May inhibit bone cell precursors |
| Osteocalcin | Binds calcium |
| Matrix-gla-protein | Inhibits mineralization |
| Bone sialoprotein | Binds to integrins, may assist cancer cells |
| Osteopontin | Increases angiogenesis (makes new blood vessels) which enhances bone resorption in some situations |
| Matrix extracellular protein | May induce a bone disease called osteomalacia |
| Fibronectin knock-out | Lethal |
| Osteonectin knock-out | Osteoporosis |
| Thrombospondin knock-out | Dense bones |
| Osteocalcin knock-out | Bones seem normal |
| Matrix-gla-protein knock-out | Normal bones but calcified blood vessels |
| Osteopontin knock-out | Resistance to PTH and removal of ovaries |
| PTH stimulates | osteoclastic bone resorption indirectly to release calcium from bone. |
| PTH stimulates | stimulates bone formation that is coupled to bone resorption. |
| PTH increases | increases renal tubular reabsorption of calcium. |
| PTH | stimulates the renal production of 1,25 dihydroxyvitamin D to increase calcium absorption from the intestine. |
| PTH enhances | renal phosphate and bicarbonate excretion. |
| A decrease in serum calcium concentration and an increase in serum phosphorous concentration will | stimulate PTH secretion |
| Calcitonin is a peptide hormone | produced by cells within the thyroid gland |
| Calcitonin secretion is stimulated by | high blood calcium concentrations |
| Calcitonin | acts as a physiologic antagonist to PTH |
| Osteoclasts have receptors for … | calcitonin, but the effects of bidning are are transient. |
| Calcitonin inhibits | osteoclast resorption |
| Calcitonin delays | delays calcium absorption from the intestine |
| Calcitonin increases | calcium urinary excretion |
| gastrointestinal absorption of calcium and phosphorus. | Vitamin D promotes |
| is necessary for bone mineralization. | Vitamin D |
| stimulates bone resorption when given in high doses. | Vitamin D |
| Increase bone resorption | Parathyroid hormone |
| Increase bone resorption | Glucocorticoids |
| Increase bone resorption | Thyroid Hormone |
| Increase bone resorption | Vitamin D metabolites in high doses |
| Decrease Bone Resorption | Calcitonin |
| Decrease Bone Resorption | Gonadal Steriods |
| Increase bone formation | Growth hormone |
| Increase bone formation | Vitamin D metabolites |
| Increase bone formation | Gonadal steroids |
| Decrease Bone Formation | Glucocorticoids |
| Ergocalciferol | Vitamin D2 |
| Cholecalciferol | Vitamin D3 |
| calcifediol | Product of 25-hydroxylation in liver |
| calcitriol | Product of 1-hydroxylation in kidney |
| DHT—dihydrotachysterol | Vitamin D analog no 1-OH needed for activation, does need liver 25-OH |
| 1a-Hydroxycholecalciferol | Vitamin D analog already has 1-OH group |
| Doxercalciferol (1-hydroxyvitamin D2) | Vitamin D analog, does need liver 25-OH |
| 22-oxacalcitriol MOA | suppressor of PTH gene expression, limited action on intestine and bone |
| 22-oxacalcitriol therapeutics | used in chronic renal failure, primary hyperparathyroidism |
| 22-oxacalcitriol indications | low affinity for serum binding protein leads to longer half-life than calcitriol |
| Estrogens | act on osteoblasts to decrease osteoclast recruitment and activation |
| Calcitonin | direct effect on osteoclast to decrease bone resorption |
| Calcitonin | decrease calcium and phosphate reabsorption in kidney |
| Glucocortiocoids | antagonize Vitamin D stimulated intestinal calcium absorption |
| stimulate renal calcium excretion | Glucocortiocoids |
| increase PTH stimulated bone resorption | Glucocortiocoids |
| block bone collagen synthesis | Glucocortiocoids |
| bisphosphonates indications | Non-hormonal Tx for osteoperosis |
| bisphosphonates MOA | retard formation and dissolution of hydroxyapatite imbibed by osteoclasts |
| close to pyrophosphate | bisphosphonates structure |
| bisphosphonate metabolism | metabolized into ATP analog, accumulates in osteoclasts |
| etidronate and tiludronate side effects | impairs cell function and viability, induces apoptosis |
| alendronate MOA | inhibition of protein prenylation important for osteoclast function |
| alendronate | less side effect of decrease bone mineralization |
| gastric irritation common with all bisphosphonates except | etidronate |
| zoledronate toxicity | some renal toxicity |
| Estrogens decrease | IL-6, IL-1, TNF-? |
| Estrogens increase | IGF-1, BMP-6, TGF-? |
| plicamycin | cytotoxic antibiotic that also decreases plasma [Ca++] by inhibiting bone resorption |
| gallium nitrate | inhibits bone resorption, renal toxicity |
| oral sodium phosphate | binds free ionized calcium, high risk procedure |
| edetate disodium (EDTA) | calcium chelator, high risk procedure |
| cinacalcet MOA | inhibits PTH secretion by lowering the[ Ca++] at which PTH secretion is suppressed |
| cinacalcet | calcimimetic |
| cinacalcet indications | 1' and 2' hyperparathyroidism and hypercalcemia of parathyroid carcinoma |
| thiazide diuretics | inhibit renal calcium stone formation by reducing renal calcium excretion |
| fluoride | both acute and chronic toxicities limit use |
| fluoride MOA | accumulates in bone and teeth may stabilize hydroxyapatite |
| Hypercalcemia tx | Bisphosphonates, calcitonin, plicamycin, gallium nitrate, phosphates, glucocorticoids |
| Osteoporosis tx | Bisphosphonates, calcitonin, vit D analogs, Ca+ supplements, thiazides, intermittent teriparatide |
| Paget’s disease tx | Calcitonin, bisphosphonates |
| Hypoparathyroidism tx | Vitamin D analogs |
| Hyperparathyroidism tx | oxacalcitriol, cinacalcet |
| renal osteodystrophy tx | Vitamin D analogs, phosphate binders |
| colchicine indications | Acute Gout |
| colchicine MOA | inhibits migration and phagocytic actions of granulocytesand PMN elaboration of inflammatory glycoprotein |
| colchicine side effects | nausea, vomiting, diarrhea, abdominal pain ; affects rapidly proliferating epithelial cells |
| allopurinol MOA | parent drug and metabolite alloxanthine inhibit xanthine oxidase, ¯ uric acid synthesis |
| inhibits metabolism of azathioprine, 6-mercaptopurine | allopurinol drug interaction: |
| tx for chronic gout with impaired renal function | allopurinol |
| probenecid MOA | uricosuric agent, inhibits uric acid renal tubular reabsorption |
| probenecid drug interactions | multiple due to blocking renal secretion |
| sulfinpyrazone indications | chronic gout tx with no anti-inflammatory or analgesic properties |
| probenecid | developed to inhibit renal tubular secretion of penicillin |
| colchicine side effects | interferes with mitotic spindle function |
| methotrexate at doses used for arthritis, effects probably due to: | inhibition of aminoimidazolecarboxamide ribonucleotide transformylase and thymidylate synthase |
| methotrexate anti-inflammatory actions include : | decrease leukocyte adhesion to endothelial cells |
| may inhibit transmethylation reactions of phospholipids and polyamines altering lymphocyte and neutrophil function/chemotaxis | methotrexate |
| methotrexate at doses used for arthritis, most common adverse effects: | nausea and mucosal ulcers, hepatotoxicity, monitor liver enzymes, after 5 years of use - -liver biopsy |
| alkylating agents/cross link DNA | cyclophosphamide, chloramabucil |
| toxic effects of cyclophosphamide, chloramabucil | bone marrow suppression, infertility, increased risk of infections and neoplasia |
| azathioprine MOA | converted to 6-mercaptopurine, inhibits de novo purine synthesis |
| azathioprine primary targets | T and B cells |
| any rapidly growing cell population | azathioprine toxicity |
| mycophenolate mofetil MOA | inhibits inosine monophosphate dehydrogenase de novo purine biosynthesis |
| interferes with leukocyte adhesion by inhibition of E- and P-selectin expression | mycophenolate mofetil MOA |
| T and B cell sensitive due to lack of salvage pathway | mycophenolate mofetil MOA |
| sulfasalazine MOA | acts by scavenging free radicals and as COX inhibitor and dihydrofolate reductase inhibitor |
| leflunomide | pro-drug; inhibits de novo ribonucleotide synthesis and triggers p53 translocation to nucleus arresting cells in G1 phase |
| leflunomide adverse effects | diarrhea as adverse effect in about 25% patients some liver toxicity |
| cyclosporine MOA | inhibits calineurin phosphatase activity, decrease transcription of cytokines in T-cells |
| somewhat selective effect on T-cells | cyclosporine indications |
| cyclosporin toxicity | Renal |
| chloroquine and hydroxychloroquine MOA | unclear MOA in arthritis, may decrease T-cell response to mitogens |
| chloroquine and hydroxychloroquine effects | decrease leukocyte chemotaxis, stabilize lysosomal membranes, trap free radicals, general decrease in DNA and RNA synthesis |
| chloroquine and hydroxychloroquine toxicity | fairly well tolerated |
| penicillamine MOA | unclear MOA in arthritis, may decrease DNA, collagen, and mucopolysaccharides synthesis |
| penicillamine | rarely used, toxic - - kidney damage, leukopenia, thrombocytopenia,and aplastic anemia |
| gold compounds toxicity: | lesions of skin and mucous membranes GI effects, renal toxicity, hematologic abnormalities |
| gold compounds indications: | use is in decline, second line drugs, use is in decline, second line drugs, |
| gold compounds MOA: | Unclear MOA, inhibit PMN and T-cell fxn may inhibit release of histamine, prostaglandins, leukotrienes |
| auranofin: | oral administration, lipid soluble |
| aurothiomalate, aurothioglucose | IM, water soluble |
| Anti- TNF-a drugs | Etanercept, Infliximab, Adalimumab |
| Anti- TNF-a drugs therapeutics | agents must given by injection, screen for latent or active tuberculosis |
| Anti- TNF-a drugs adverse effects | increase risk of macrophage dependent infections |
| Etanercept | recombinant fusion protein consisting of two soluble TNF receptor regions linked to Fc portion of human IgG |
| Infliximab | chimeric monoclonal antibody with variable murine region linked to constant human region specific against human TNF |
| Adalimumab | Recombinant human anti-TNF monoclonal antibody |
| Rituximab MOA | monoclonal antibody that targets CD20 (on B-cells) |
| Rituximab main use: | treatment of rheumatoid arthritis refractory to anti-TNF agents |
| Abatacept MOA | inhbt T-cell actvtn: binds CD80 (on APCs) prvnts interaction w/CD28 (on T cells) |
| Immunoadsorption apheresis | may down-regulate B-cell function by release of small amounts of immune complexes consisting of IgG and staph protein A |
| Immunoadsorption apheresis adverse effects: | fever, chills, joint pain and swelling,hypotension from IV, pulmonary emboli and sepsis |
| Immunoadsorption apheresis indications: | generally used in patients who have failed other therapies for rheumatoid arthritis |
| Dietary manipulation of rheumatoid arthritis inflammation : | Increase intake of eicosapentaenoic acid (EPA)(20:5, fish oil) |
| Cyclooxygenase-derived metabolites of EPA… | are much less potent mediators of inflammation than the corresponding metabolites of AA (prostaglandins) |
| When a depolarization signal arrives, | Ca2+ exits the SR via ryanodine-sensitive Ca2+ channel |
| Creatine kinase is an enzyme found in | sarcoplasm and as component of M-line of H band |
| Creatine kinase | catalyzes transfer of phosphate from creatine phosphate to ADP |
| Ca2+ binds troponin C and.. | causes conformational change in troponin-tropomyosin complex |
| When myelinated axons reach the perimysium, they lose their myelin sheath but... | the presynaptic buttons remain covered with Schwann cell processes |
| Synaptic buttons occupy a depression of the muscle fiber, called the | primary synaptic cleft |
| Acetylcholine receptors are located at the | crests of the deep junctional folds (secondary synaptic clefts) |
| voltage-gated Na+ channels are located | down into the secondary synaptic clefts |
| The basal lamina of the synaptic cleft contains... | acetylcholinesterase, which inactivates acetylcholine |
| The basal lamina covering the Schwann cell becomes | continuous with the basal lamina of the muscle fiber |
| T tubules.. | form rings around every sarcomere of every myofibril at the A-I junction |
| An excitation-contraction signal is generated by | acetylcholine |
| that the sarcoplasm of a skeletal muscle cell is packed with | myofibrils (each consisting of a linear repeat of sarcomeres) with abundant mitochondria between |
| The length of the thick and thin filaments does not change during muscle contract | the length of the A band and the distance between the Z disk and the adjacent H band are constant |
| The length of the sarcomere decreases because thick and thin filaments slide past each other | (the size of the H band and I band decrease) |
| Tropomyosin | two nearly identical à-helical polypeptides twisted around each other |
| Tropomyosin | runs in the groove formed by F-actin strands |
| Troponin | a complex of three proteins |
| Troponin I | inhibits the binding of myosin to actin |
| Troponin C | binds Ca2+ and is found only in striated muscle |
| Troponin T | binds the complex to tropomyosin |
| Myosin | the major component of the thick filament |
| Myosin | binds to F-actin-the major component of the thin filament-in a reversible fashion |
| Myosin | has adenosine triphosphatase (ATPase) activity (it hydrolyzes ATP) |
| Nebulin | is associated with thin (actin) filaments; it inserts into the Z disk |
| Titin | associates with thick (myosin) myofilaments and inserts into the Z disk, extending to the bare zone of the myosin filaments, close to the M line |
| Nebulin | acts as a template for determining the length of actin filaments |
| Titin | controls the assembly of the myosin myofilament by acting as a template |
| Titin | has a role in sarcomere elasticity by forming a spring-like connection between the end of the thick myofilament and the Z disk |
| Z disks | are the insertion site of actin filaments of the sarcomere |
| à-actinin | anchors the barbed end of actin filaments to the Z disk |
| Desmin | forms intermediate filaments that extend from the Z disk of one myofibril to the adjacent myofibril, forming a supportive latticework |
| Desmin filaments also extend from | the sarcolemma to the nuclear envelope |
| costameres | specialized sarcolemma-associated plaques |
| Costameres act in concert with the dystrophin-associated protein complex to | transduce contractile force from the Z disk to the basal lamina |
| plectin filaments | Link Desmin filaments to the Z disk and to each other |
| Desmin, plectin, and àB-crystallin | form a mechanical stress protective network at the Z-disk level |
| The heat shock protein àB-crystallin | protects Desmin filaments from stress-induced damage |
| The barbed end of actin filaments | inserts into the Z disk |
| G-actin monomers bind to each other in a head-to-tail fashion, thus... | giving the filament polarity, with barbed (plus) and pointed (minus) ends |
| F-actin is composed of | globular monomers (G-actin) |
| The Z disk forms a transverse sarcomeric scaffold that serves to ... | ensure the efficient transmission of the generated force. |
| Thin myofilaments | measure 7 nm in width and 1 ?m in length |
| Thin myofilaments | form the I band which is light |
| Thick filaments | measure 15 nm in width and 1.5 ?m in length |
| Thick filaments | found in the A band which is dark |
| The A band is bisected by | a light region called the H band |
| The major component of the H band | creatine kinase, which catalyzes the formation of ATP from creatine phosphate and adenosine diphosphate (ADP) |
| creatine phosphate | maintains steady levels of ATP during prolonged muscle contraction |
| Runs through the midline of the H band at the middle of each A band | the M line |
| M-line striations correspond to | The alignment of the lateral assembled tails of myosin |
| Thin filaments insert into | each side of the Z disk, whose components include à-actinin |
| Skeletal muscle cells are formed in the embryo by the fusion of myoblasts that produce | a postmitotic, multinucleated myotube |
| The site of contact of the T tubule with the sarcoplasmic reticulum cisternae | triad |
| Myofibril | chain of sarcomeres |
| The tendon anchors into a bone through | periosteal Sharpey's fibers |
| epimysium | a dense connective tissue layer ensheathing the entire muscle |
| perimysium | derives from the epimysium and surrounds bundles or fascicles of muscle cells |
| endomysium | a delicate layer of reticular fibers and extracellular matrix surrounding each muscle cell |
| Blood vessels and nerves use these connective tissue sheaths to | reach the interior of the muscle |
| at each end of a muscle the myotendinous junction is formed by the | Interdigitatation of radiating-muscle fascicles with regular dense connective tissue of the tendon |
| the terminal differentiation of the muscle cell precursor- | triggered by myogenin and MRF4. |
| attach to the surface of the myotubes before a basal lamina surrounds the satellite cell and myotube | Satellite cells |
| MyoD expression | induces the proliferation of satellite cells |
| Satellite cells | muscle maintenance, repair, and regeneration in the adult |
| Satellite cells | are mitotically quiescent in the adult, but can reassume self-renewal and proliferation in response to stress or trauma |
| receptor expressed on the surface of quiescent satellite cells encoded by a proto-oncogene | c-Met receptor |
| myogenic precursor cells | descendants of the activated satellite cells which undergo multiple rounds of cell division before they can fuse with existing or new myofibers |
| HGF-c-Met complex | upregulates a signaling cascade leading to proliferation of the satellite cells and the expression of Myf5 and MyoD |
| F-actin | the thin filament of the sarcomere, is double-stranded and twisted |
