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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 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; Ca3(PO4)2 deficiency • Osteoporosis ↑ loss total bone mass; resorption > formation
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 • 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 84 year old Female (w/ vertebral fracture) 52 year old Female Borah et al Anat. Rec.(2001)
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 Postmenopausal = cancellous bone; vertebrae, metaphyses; endocrtical surfaces of long bone Alcoholic = decreased total remodeling of both cancellous and cortical (compact) bone
Ca++ Regulation http://www.endocrinesurgery.net.au/parathyroidfunction/
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 cells and bone marrow cells produce osteoprotegerin (OPG) inhibited by PTH • Blocks RANKL • Prevents osteoclast development & function • Bone breakdown decreases • Bones grow
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 • 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 • 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 Tatyana Vikulina, et. al. PNAS 107(31):13848 2010
Bone Mineral Density n = 4 n = 4 n = 6 Average ± SD, *P ≤ 0.05 by Mann-Whitney test
Longitudinal trabecular X-sectional trabecular Cortical Scale bar = 1 mm
A. CTx = C-terminal telopeptide (n = 4) B. Serum osteocalcin (n = 4) TRAP = Tartrate resistant acid phosphatase
G. OCs / BS (n = 4) H. OCs Surface / BS (n = 4) Mineralized bone stains orange/pink (H & E Stain)
C. Role of TNFα in OCgenesis D. OC precursors E. Histogram = macrophages; Bar graph RT-qPCR for M-CSF
RT-qPCR analysis of OPG and RANKL expression from total Spleen and Bone Marrow
RT-qPCR analysis of OPG and RANKL expression from B cells and B cell-depleted tissues
HAART Effects • 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 too! AIDS 23:1297-1310, 2009
Healing—Hematoma Formation Blood vessels tear and bleedHematoma HematomaFibrin meshwork Inflammatory cell, influx, fibroblast ingrowth, and capillary bud formation
Healing—Fibrous Callus Infiltrating capillaries procallus Fibroblasts (periosteum, endosteum, red marrow) fibrocartilaginous “glue” 2-3 weeks
Healing—Bony Callus Osteogenic cells (MSCs) Osteoblasts Osteoblasts spongy bone trabeculae Bony sheath covers fibrous callus Spongy bone calcifies 3-4 weeks to months
Healing—Remodeling Osteoclasts remove dead bone Compact replaces spongy bone (fracture periphery) Thickened area remains