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