Selected Topics in Biochemistry: Bone, Endotheliumium adn Adipose Tissue

1. Selected Topics in Biochemistry: Bone, Endotheliumium adn Adipose Tissue František Duška

2. Biochemistry of Bone Case Mechanism of Bone Remodeling Calcium and Phosphate Biochemical Markers of Bone Metabolism

3. 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

4. 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

5. 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

7. 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

9. 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

11. Bone aand metabolism of Ca2+

12. 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

13. Laboratory markers of bone metabolism • S-Ca2+ • total 2,25-2,75 mM • ionized: 50%, i.e. 1.3 mM • S-phosphate • appr. 1mM

14. Laboratory markers of bone metabolism Markers 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

15. Collagen I COOH ŠTĚPENÍ PŘI SYNTÉZE collagenU NH2 karboxyterminální propeptid procollagenu (PICP) STĚPENÍ PŘI DEGTADACI collagenU karboxyterminální telopeptid collagenu

16. Common bone disorders • Osteoporosis = loss of both inorganic and organic bone matrixfractures • 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

17. Case No. 1 Densitometry: bone density -2.1 SD Elfo of plasma proteins : normal

18. Case No. 1 • Conclusion: primary osteoporosis, type II, „fast-looser“ • Therapy: vit D 600IU/day, Ca-effercescens 1g/day, palmidronate (bone resorption inhibitor)

19. 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?

20. Endotheliumium Endotheliumium function Case

21. 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

25. 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..

26. 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

29. Case No. 2 • Dg: anaphylactic reaction due to exposure to peanuts

31. Case No. 2 • Alergická reakce vede ke generalizované aktivaci Endotheliumu: • Vyšší permeabilita způsobí • otok kůže a sliznickopřivka, Quinckeho edém • otok dýchacích cest  bronchiokonstrikce, dušnost • únik tekutiny z cév hypovolémie • Vasodilatace  hypotenze, šok

32. Case No. 2 • Therapy: • i.v. line put during transport, hydrocortison + epinephrinei.v., volumexpansion R1/1 • vital function stable during transport

34. 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)

35. 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

36. Endothelium - závěr • List endothelium functions. • Describe endothelium-mediated vasodilation. • What is edothelium activation?

37. Adipose Tissue Storage function: lipolysis and lipogenesis Endocrine and regulatory function Case

38. 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)

39. Adipose Tissue: function II. • Endokrinní function: • leptin = signál o stavu tukových zásob • anorexigenní působení • 167 AK, ob gen • adiponectin • TNF-alfa • rezistin

41. 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

42. 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

43. 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

44. Case No. 3

45. 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

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