title: Select HIV protease inhibitors alter bone and fat metabolism ex vivo.
abstract: Human immunodeficiency virus (HIV) therapies have been associated with alterations in fat metabolism and bone mineral density. This study examined the effects of HIV protease inhibitors (PIs) on bone resorption, bone formation, and adipocyte differentiation using ex vivo cultured osteoclasts, osteoblasts, and adipocytes, respectively. Osteoclast activity, measured using a rat neonatal calvaria assay, increased in the presence of nelfinavir (NFV; 47.2%, p = 0.001), indinavir (34.6%, p = 0.001), saquinavir (24.3%, p = 0.001), or ritonavir (18%, p < 0.01). In contrast, lopinavir (LPV) and amprenavir did not increase osteoclast activity. In human mesenchymal stem cells (hMSCs), the PIs LPV and NFV decreased osteoblast alkaline phosphatase enzyme activity and gene expression significantly (p < 0.05). LPV and NFV diminished calcium deposition and osteoprotegrin expression (p < 0.05), whereas the other PIs investigated did not. Adipogenesis of hMSCs was strongly inhibited by saquinavir and NFV (>50%, p < 0.001) and moderately inhibited by ritonavir and LPV (>40%, p < 0.01). Expression of diacylglycerol transferase, a marker of adipocyte differentiation, decreased in hMSCs treated with NFV. Amprenavir and indinavir did not affect adipogenesis or lipolysis. These results suggest that bone and fat formation in hMSCs of bone marrow may be coordinately down-regulated by some but not all PIs.
authors.affiliation: Department of Metabolic Diseases, GlaxoSmithKline Inc., Research Triangle Park, North Carolina 27709, USA.
authors.forename: Renu G
authors.initials: RG
authors.lastname: Jain
authors.forename: James M
authors.initials: JM
authors.lastname: Lenhard
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001842:Bone and Bones / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002219:Carbamates; D002478:Cells, Cultured; D015536:Down-Regulation; D005223:Fats / Q000378:metabolism*; D005663:Furans; D006023:Glycoproteins / Q000096:biosynthesis; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D019469:Indinavir / Q000494:pharmacology; D061466:Lopinavir; D008648:Mesoderm / Q000166:cytology; D019888:Nelfinavir / Q000494:pharmacology; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D053244:Osteoprotegerin; D011744:Pyrimidinones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis; D018124:Receptors, Tumor Necrosis Factor; D019438:Ritonavir / Q000494:pharmacology; D019258:Saquinavir / Q000494:pharmacology; D012886:Skull / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D002219:Carbamates; D005223:Fats; D005663:Furans; D006023:Glycoproteins; D017320:HIV Protease Inhibitors; D053244:Osteoprotegerin; D011744:Pyrimidinones; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D013449:Sulfonamides; C506030:TNFRSF11B protein, human; C506032:Tnfrsf11b protein, rat; D061466:Lopinavir; C095108:amprenavir; D019469:Indinavir; D019888:Nelfinavir; D019258:Saquinavir; D019438:Ritonavir; D002118:Calcium