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Alcohol, HIV, ART, & Bone Metabolism. Robert W. Siggins 24 February 2012 rsiggi@lsuhsc.edu. Metabolic Bone Disorders Overview. Origin in disrupted bone remodeling process Osteomalacia & rickets  bone softening from ↓ bone mineralization; Ca 3 (PO 4 ) 2 deficiency

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Alcohol hiv art bone metabolism

Alcohol, HIV, ART, & Bone Metabolism

Robert W. Siggins

24 February 2012

rsiggi@lsuhsc.edu


Metabolic bone disorders overview
Metabolic Bone Disorders Overview

  • Origin in disrupted bone remodeling process

  • Osteomalacia & rickets  bone softening from ↓ bone mineralization; Ca3(PO4)2 deficiency

  • Osteoporosis ↑ loss total bone mass; resorption > formation


Osteopenia and osteoporosis
Osteopenia and Osteoporosis

  • Osteopenia

    • Decreased bone

    • Not a diagnosis; Radiographic description

    • Etiology  Osteoporosis, osteomalacia, cancers, endocrine disorders

  • Osteoporosis

    • Decreased bone mass

    • Decreased cancellous (spongy) bone strength


Osteoporosis
Osteoporosis

  • Porous bone

  • Poorly mineralized bone

  • Bone density

    • Normal bone

      • 833 mg/cm2

    • Osteopenic bone

      • 648 – 833 mg/cm2

    • Osteoporosis

      • < 648 mg/cm2

  • Diagnosis = 2.5 SD from normal female

Femoral Head


3 d micro ct healthy vs osteoporotic bone
3-D Micro CT:Healthy vs Osteoporotic Bone

84 year old Female

(w/ vertebral fracture)

52 year old Female

Borah et al Anat. Rec.(2001)


Osteoporosis1
Osteoporosis

  • Potential causes

    • Decreased levels of estrogen and testosterone

    • Alcohol Abuse

    • HIV / HAART

    • Inadequate levels of vitamins D and C, or Mg++

    • Demonstrated by reduced bone mass / density and an imbalance of bone resorption and formation

  • Bone histology is usually normal but it lacks structural integrity




Osteoporoses of long bones
Osteoporoses of Long Bones

Postmenopausal = cancellous bone; vertebrae, metaphyses; endocrtical surfaces of long bone

Alcoholic = decreased total remodeling of both cancellous and cortical (compact) bone


Ca regulation
Ca++ Regulation

http://www.endocrinesurgery.net.au/parathyroidfunction/


Normal bone remodeling
Normal Bone Remodeling

  • Osteoblasts “bone building” cells

  • They control bone remodeling by:

    • Laying down new bone

    • Secrete RANK ligand (RANKL) that controls osteoclasts “bone breaking” cells

  • Normally, bone formation and breakdown are balanced:

    • Replace damaged bone

    • Maintain amount & density of bone


Bone growth
Bone Growth

  • Bone cells and bone marrow cells produce osteoprotegerin (OPG)  inhibited by PTH

    • Blocks RANKL

    • Prevents osteoclast development & function

    • Bone breakdown decreases

    • Bones grow







Alcohol hiv art bone metabolism

Osteocytes  50 cellular projections; extend throughout bone matrix; connect osteocytes to osteocytes & to cells at the bone surface  form the lacunocanalicular network

Nat med 17(10):1235, 2011


Matrix embedded bm cells
Matrix Embedded BM Cells

  • Osteocytes

    • Floxed RANKL mouse crossed with osteocyte specific Cre mouse

    • No change in total bone RANKL mRNA or circulationg RANKL

    • >70% decrease in OC number

Nat med 17(10):1235, 2011


Alcohol and bone metabolism
Alcohol and Bone Metabolism

  • Osteoblast #, osteoid synthesis, osteoid mineralization rate ↓ in human alcoholics compared to nonalcoholic controls; Impaired polyamine pathway (Klein and Carlos, 1995)

  • Cortical bone loss  decreased bone formation rate (BFR) (Hogan et al., 1997)

  • Young adult-to-adult rats  starting age of ethanol feeding increases, cancellous bone loss > cortical bone

  • Bone marrow in osteoporotic bone ↓ osteogenic cells, ↑ adipocytes (Burkhardt et al., 1987)

ACER 29(12):2077, 2005


Alterations in the immuno skeletal interface drive bone destruction in hiv 1 transgenic rats

Alterations in the immuno-skeletal interface drive bone destruction in HIV-1 transgenic rats

Tatyana Vikulina, et. al.

PNAS 107(31):13848 2010



Alcohol hiv art bone metabolism

Bone Mineral Density

n = 4

n = 4

n = 6

Average ± SD, *P ≤ 0.05 by Mann-Whitney test


Alcohol hiv art bone metabolism

Longitudinal

trabecular

X-sectional

trabecular

Cortical

Scale bar = 1 mm


Alcohol hiv art bone metabolism

A. CTx = C-terminal telopeptide (n = 4)

B. Serum osteocalcin (n = 4)

TRAP = Tartrate resistant acid phosphatase


Alcohol hiv art bone metabolism

G. OCs / BS (n = 4)

H. OCs Surface / BS (n = 4)

Mineralized bone stains orange/pink (H & E Stain)



Alcohol hiv art bone metabolism

C. Role of TNFα in OCgenesis

D. OC precursors

E. Histogram = macrophages; Bar graph RT-qPCR for M-CSF




Antiretroviral therapies

Antiretroviral Therapies and B cell-depleted tissues


Alcohol hiv art bone metabolism

http://aidsinfo.nih.gov/guidelines and B cell-depleted tissues


Haart effects
HAART Effects and B cell-depleted tissues

  • N(n)RTIs inhibit mitochondria 

    • Ox Stress?

    • Chronic lactic acidosis?

  • Protease Inhibitors 

    • Enhance OCgenesis and activity

    • Decrease OBgenesis and activity

  • Impaired Vit D metabolism 

    • Osteomalacia  Osteopenia

AIDS 23:1297-1310, 2009


Alcohol hiv art bone metabolism

Alcohol too! and B cell-depleted tissues

AIDS 23:1297-1310, 2009


Questions and break time

Questions and Break Time! and B cell-depleted tissues


Healing hematoma formation
Healing—Hematoma Formation and B cell-depleted tissues

Blood vessels tear and bleedHematoma

HematomaFibrin meshwork

Inflammatory cell, influx, fibroblast ingrowth, and capillary bud formation


Healing fibrous callus
Healing—Fibrous Callus and B cell-depleted tissues

Infiltrating capillaries procallus

Fibroblasts (periosteum, endosteum, red marrow) fibrocartilaginous “glue”

2-3 weeks


Healing bony callus
Healing—Bony Callus and B cell-depleted tissues

Osteogenic cells (MSCs)  Osteoblasts

Osteoblasts  spongy bone trabeculae

Bony sheath covers fibrous callus

Spongy bone calcifies

3-4 weeks

to months


Healing remodeling
Healing—Remodeling and B cell-depleted tissues

Osteoclasts remove dead bone

Compact replaces spongy bone (fracture periphery)

Thickened area remains