selected topics in biochemistry: bone, endotheliumium adn adipose tissue františek duška
TRANSCRIPT
Selected Topics in Biochemistry: Bone, Endotheliumium adn Adipose Tissue
František Duška
1. Case2. Mechanism of Bone Remodeling3. Calcium and Phosphate4. Biochemical Markers of Bone Metabolism
Function of Bone
•Mechanical▫lever for musscles▫protects bone marrow
•Calcium and phosphate store (cca 1kg) ▫influences their metabolism
•Buffer▫long lasting MAC (renal failure etc.)
releases phosphate and bicarbonate▫contributes to ABB stability, even at the
price of bone damage
Case No. 1
•Current problem: female, 59 yrs, strong pain at right groin after a minor fall
•History: no serious diseases, no medication, only analgesics for backache (worsen for 3 yrs). Climacterium at 44, no HRT
•Works as officer, no abuse
Case No. 1
•On examination: BP 150/90, HR 100/min, Breaths 20/min, supine: right leg shortened, in abduction and external rotation, tenderness oevr major trochanter, passive movement of right hip painful
•Othervise normal physical examination
Case No. 1
•Dg: Comminutive intertrochanteric fracture of right hip after minor trauma, osteoporosis
•After hip replacement (CCEP) transferred for examination and tratment of osteoporosis
Bone composition:
•Cells:▫synthetizing new bone: osteoblasts,
osteocytes▫beaking down old bone: osteoclasts
•Intercellular matrix:▫organic: collagen type I + non-collagenní
proteins (e.g. osteocalcin)▫inorganic: hydroxyapatite: Ca10(PO4)6(OH)2
•Terms: lamelar/trabecular bone
Bone aand metabolism of Ca2+
Faktory ovlivňující mtb. bonei• PTH: zvyšuje resorpci i
syntézu: výsledek = zvýšené uvolňování Ca2+
• kalcitonin: inhibuje osteoklasty, snižuje resorpci bonei: výsledek = zvýšené ukládání Ca2+ do bonei
• estrogeny: dtto• IGF-1: zodp. za růst boneí • kalcitriol: zajišťuje
dostupnost Ca2+ pro bone• glukokortikoidy: snižují
novotvorbu bonei
Laboratory markers of bone metabolism
•S-Ca2+
▫total 2,25-2,75 mM▫ionized: 50%, i.e. 1.3 mM
•S-phosphate▫appr. 1mM
Laboratory markers of bone metabolismMarkers of bone synthesis Markers of bone degradation
• S-ALP bone izoenzyme• U-terminal propeptids of
collagen type I• S-osteocalcin
• S-ACP bone izoenzyem (tartate resistant)
• U-karboxytermina telopeptide of collagen
• U-hydroxyproline• U-deoxypyridinoline• Ca2+ urine waste/24 hrs
Collagen I
NH2
COOH
karboxyterminální propeptid procollagenu (PICP)
ŠTĚPENÍ PŘI SYNTÉZE collagenU
STĚPENÍ PŘI DEGTADACI collagenU
karboxyterminální telopeptid collagenu
Common bone disorders
•Osteoporosis = loss of both inorganic and organic bone matrixfractures▫primary = cause is complex and unknown▫secondary= cause identifiable
•Osteomalacia (adult)/rachitis (childhood) = loss of inorganic bone mass bone softening, deformities▫typical cause: lack of vit. D
Case No. 1Lab. value comment
S-Ca2+ =2.2 mM
S-P =1,12 mM normal
S-ALP = 24 IU (norma 10-22 IU)
S-ACP = 31 ug/ml (norma=7-28)
S-PTH274 ng/l (20-300 ng/l) normal
Densitometry: bone density -2.1 SDElfo of plasma proteins : normal
Case No. 1
•Conclusion: primary osteoporosis, type II, „fast-looser“
•Therapy: vit D 600IU/day, Ca-effercescens 1g/day, palmidronate (bone resorption inhibitor)
Conclusion: bone metabolism
•What are functions of a bone?•What a bone consists of? Which
compounds can be used diagnostically?•Which hormones regulate plasma Ca2+?•Which routinelly assayed lab values can
point out to bone disorder?
1. Endotheliumium function2. Case
Endothelium
•= epithelium of inner vessel wall layer•1013 cells (1 kg!!!)•Functions:
▫anticoagulant (unwettable)▫barrier (zonulae adherentes)▫regulates vascular tonus microcirculation
macrocirculation▫metabolic: HRHL, LPL
Endothelium activation
•non-specific reaction (triggered by physical forces, infection, inflammation)
•Endothelium becomes: ▫pro-coagulant (maintaining vascular bed
integrity)▫pro-inflammatory (immune response) ▫permeable (WBC diapedesis)
•Whilst usually beneficial, it may be harmfull or life-threatening if generalized and uncontrolled..
Case No. 2•male, 41 yrs, with known peanuts allergy,
accidentally ingested nougat. After 2 min suffered paresthesia of tongue and lips. Emergency service called for increasing dyspnea.
•On addmission: ▫alert, agitatetd, dyspnea, sat 99% on O2 by
facemask, bilat. wheezes on auscultation, BP 90/40, HR 135/min, Quincke edema of lips and tongue, diffuse urtica on whole body surface
Case No. 2
•Dg: anaphylactic reaction due to exposure to peanuts
Case No. 2
•Alergická reakce vede ke generalizované aktivaci Endotheliumu:
•Vyšší permeabilita způsobí1. otok kůže a sliznickopřivka, Quinckeho
edém 2. otok dýchacích cest
bronchiokonstrikce, dušnost3. únik tekutiny z cév hypovolémie
•Vasodilatace hypotenze, šok
Case No. 2
•Therapy:▫i.v. line put during transport, hydrocortison
+ epinephrinei.v., volumexpansion R1/1▫vital function stable during transport
Case No. 2
•Therapy:▫admitted and observed in ICU, vital
function monitoring with the plan to intubate in case of worsening
▫corticoids, antihistaminics (H1 blockers)
Case No. 2
•In-hospital course: ▫rapidly improving after admission▫ after 60 mins BP 140/80 without support,
HR 78/min, no wheezing above both lungs, urtica unchanged
▫next day morning (10hrs after arrival): no subjective complaints, discharged, alergology examination recommended on out-hospital basis
Endothelium - závěr
•List endothelium functions.
•Describe endothelium-mediated vasodilation.
•What is edothelium activation?
1. Storage function: lipolysis and lipogenesis2. Endocrine and regulatory function3. Case
Adipose Tissue: function I•TAG storage (postprandial)
▫lipoprotein lipase (endothelial) activated by insulin stores TAG ingested or synthesized in the liver
▫de novo lipogenesis: from glucose•Lipolysis = release of NEFA + glycerole
(fasting)▫Hormone-sensitive lipase (IC)
inhibited by insulin activators: sympathetic NS, GH, (glucagon)
Adipose Tissue: function II.
•Endokrinní function: ▫leptin = signál o stavu tukových zásob
anorexigenní působení 167 AK, ob gen
▫adiponectin▫TNF-alfa▫rezistin
Brown Adipose Tissue
•in human only in newborns•hibernating mammals•many fatty inclusions, many mitochondria•rich adrenergic inervation•thermogenin = UCP-1 creates heat
instead ATP
Case No. 3.•Farooqi et al., N Engl J Med, 1999•Female child 8,5 yrs. Pakistani origin, parents
= brother and sister-in-law•Current problem:morbid obesity, hyperfagia
▫ nowadays 94,4 kg (above 99,9 percentile), 140 cm
•History:▫ normal birth weight, BW increases from 4
months▫ at the age of 6 liposuccion as an attempt to
improve mobility
Case No. 3
•Investigation reveals unmesurable level of plasma leptin. Cause: frameshift mutation in ob-gene
•12 trial of s.c. leptin therapy begun in 1998
Case No. 3
Case No. 3
•After 12 months of therapy:
▫weight loss 17 kg (out of which 16,1 kg fat and 0,9 kg of lean body mass)
▫mobility improved