11/20 Flashcards
Bone Cell Communication
Osteoclasts release matrix bound growth factors that can cause proliferation of osteoprogenitor cells
Ephrin ligands on differentiating osteoclasts, Eph receptors on differentiating osteoblasts, different combos inhibit/stimulate formation of one while doing the opposite to the other, combos due to differentiation state
RANKL (Receptor activator for NK-kappaB: made by osteoblasts and osteoclasts, helps osteoclasts differentiate and modulate activity
OPG (osteoprotegerin): binds RANKL and prevents it from regulating osteoclasts formation and function
Macrophage Colony Stimulating Factor: early proliferation an differentiation of osteoclasts precursors (hematopoietic stem cell and pre-osteoclasts)
Factors that Promote Bone Formation
Bone morphogenic proteins (BMP): member of TGF-beta family, promote osteoblasts formation and osteogenesis, used clinically to promote bone healing
TGF-beta: secreted by Cells or released from the matrix
IGF-1: stimulates bone formation and osteoblasts differentiation through multiple mechanisms, secreted by cells or released from matrix
Parathyroid hormone and related PTHrP: can be anabolic or catabolic, PTH is only approved anabolic therapy for osteoporosis
WNT: secreted glycoproteins that bind to extracellular receptors and promote Beta-catenin activity
NO: secreted by osteocytes, promote bone formation
Without WNT, beta-catenin undergoes proteasomal degradation
With WNT, beta-catenin is free and can travel to nucleus to promote transcription and osteoblast formation
Sclerostin: made by osteocytes, binds receptor for WNT and inhibits its activity
Osteocytes
Mechanosensor: loading like walking causes shearing forces from fluid along osteocytes membrane
Fluid shear causes production of ATP, NO, Ca
Runners have high leg bone density, swimmers normal
Contact bone lining cells and can inhibit/promote osteoblasts activity
Constitutively produce inhibitors of bone formation, mechanical loading decreases these factors
Osteocytes Mineral Homeostasis
Osteocytic osteolysis: osteocytes degrade bone somewhat to release Ca and PO4 during high mineral demand like pregnancy and lactation
FGF23: Control phosphate excretion by kidneys
Osteoclasts
Sealing Zone: actin ring that forms tight seal with matrix
Bisphosphonates inhibit cytoskeletal rearrangements in the sealing zone, osteoclasts are normally very motile
Ruffled border: specialized apical membrane that secretes HCl and cathespin K (a protease)
Anti-resorptive Therapies
Bisphosphonates (Actonel, Fossmax): interfere with Rho GTPase Signaling in osteoclasts, cant regulate actin cytoskeleton and promotes apoptosis
Disabled osteoclasts persist, taken up by osteoclasts
Denosumab (Prolia): monoclonal antibody that binds to and inhibits RANKL
Osteoclasts die
Regulators of Osteoclasts
Pro-osteoclasts-
Inflammatory cytokines: TNFalpha, IL-1, IL-6
Tumor microenvironment
Anti-osteoclasts-
Estrogen: menopause has excessive osteoclast activity
Calcitonin: inhibits osteoclast finction
Corticosteroids
Pregnenolone is precursor for aldosterone and corticosterone
90% bound to corticosteroid binding globulin, considered free if albumin bound, synthetic corticosteroids like dexamethasone bind to albumin
Levels high in morning and rise after eat, increased with pregnancy/estrogen administration and hyperthyroidism
Mechanism of Action: have nuclear receptors that are bound by hsp90, sterol ligand binding movesnt9 affect transcription at glucocorticoid receptor elements, Receptor is a homodimer, travels in blood with CBG but enters as free sterol, ligand bound receptor also interacts with transcription factors for GFs and Pro-Inflammatory cytokines
Effects of Glucocrticoids
1.Increase blood glucose supply so brain has adequate levels:
Increase glucose by gluconeogenesis, release of AA from muscle Catabolism, inhibition of peripheral glucosenuotake by muscles, and the stimulation of lipolysis
- Permissive effects: need for catecholamines to affect vascular and bronchial smooth muscle, lipolytic response of fat cells to ACTH and GFs
- Catabolic/Antianabolic: (stimulate RNA/protein synthesis in the liver but catabolic elsewhere), decreased muscle mass and thinning of skin, cause osteoporosis a Cushing’s disease, reduce growth in kids
- Anti-Inflammatory: Increase neutrophil Blood conc. due to decreased migration from blood vessels and release from bone marrow, other inflammatory cells decrease in blood since move from vascular bed to lymphoid tissue, interfere with macrophage and APC function, decrease cell mediated inflammatory products cuz impact Phospholipase A2, reduce expression of Cox-2, decrease histamine release and cause vasoconstriction by suppressing mast cell degranulation
- Other Effects: peptic ulcers, get fat, depression, antagonize vitamin D on calcium absorption, help with fetal surfactant development
Colchicine
Anti-inflammatory by binding to tubulin which prevents its polymerization and inhibits leukocyte migration/phagocytosis, inhibits leukotriene B4
More specific than NSAID but give diarrhea so use in intercritical period between attacks as prophylaxis
Adverse Effects:diarrhea, nausea, stomach feels bad, hepatic necrosis, rarely can cause bone marrow suppression and death
Dosage: intravenous stopped since life threatening, do 0.6 mg 1-3x a day for prophylaxis, for gouty attack do 1.2 mg followed by 0.6 mg after 2 hrs., Colcrys is brand name in US
Probenecid
Uricosuric drug that lowers irate in patients, don’t use if excrete large amount of uric acid
Organic acid so act at the anionic transporter of the renal tubule, decrease the net reabsorption of uric acid in the proximal tubule, Increase Risk for renal calculi
Low dose of aspirin decreases net retention of uric acid by inhibiting secretory transporter
Indications: underexcrete uric acid, when allopurinol or febuxostat is contraindicated, tophi present, use 2-3 weeks after attack
Dosage: do two 0.5 g doses at first then do 1 g
Allopurinol
Main standard of care
Reduce total uric acid by inhibiting xanthine oxidase since look like hypoxanthine, converted to alloxanthine which can further inhibit the enzyme
Adverse effects: similar to NSAID, GI problems, som skin problems, can bind to cataracts
Use caution with chemotherapeutic agents
Dosage: normally 300 mg daily
Febuxostat
Non-purine xanthine oxidase inhibitor
Adverse effects: GI problems
Dosage: 80 mg
Good if have problems with allopurinol
Pegloticase
Uricase attached to mPEG that prolongs half life and diminishes immune response
Adverse effects: infusion reactions and gout flare, small kidney stone, arthalgia, nausea, anemia, less commonly RTI and UTI
Can make antibody against it
Dosage: 8 mg IV every 2 weeks
Gout Drugs
- Acute-
NSAID, colchicine, corticosteroids
NSAID is first line for acute gout, don’t use aspirin sinc cause renal retention of uric acid, use prednisone, for severe symptomatic gout
- Chronic-
Uricosuric, xanthine oxidase inhibitors, colchicine if also take allopurinol
