Alterations in the immuno-skeletal interface drive bone destruction in HIV-1 transgenic rats.
Osteoporosis and bone fractures are increasingly recognized complications of HIV-1 infection. Although antiretroviral therapy itself has complex effects on bone turnover, it is now evident that the majority of HIV-infected individuals already exhibit reduced bone mineral density before therapy. The mechanisms responsible are likely multifactorial and have been difficult to delineate in humans. The HIV-1 transgenic rat recapitulates many key features of human AIDS. We now demonstrate that, like their human counterparts, HIV-1 transgenic rats undergo severe osteoclastic bone resorption, a consequence of an imbalance in the ratio of receptor activator of NF-kappaB ligand, the key osteoclastogenic cytokine, to that of its physiological decoy receptor osteoprotegerin. This imbalance stemmed from a switch in production of osteoprotegerin to that of receptor activator of NF-kappaB ligand by B cells, and was further compounded by a significantly elevated number of osteoclast precursors. With the advancing age of individuals living with HIV/AIDS, low bone mineral density associated with HIV infection is likely to collide with the pathophysiology of skeletal aging, leading to increased fracture risk. Understanding the mechanisms driving bone loss in HIV-infected individuals will be critical to developing effective therapeutic strategies.
Vikulina
Tatyana
T
Division of Endocrinology and Metabolism and Lipids, Emory University School of Medicine, Atlanta, GA 30322, USA.
Fan
Xian
X
Yamaguchi
Masayoshi
M
Roser-Page
Susanne
S
Zayzafoon
Majd
M
Guidot
David M
DM
Ofotokun
Ighovwerha
I
Weitzmann
M Neale
MN
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015519:Bone Density; D001862:Bone Resorption / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D015497:HIV-1 / Q000276:immunology*; D008297:Male; D053245:RANK Ligand / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D055647:Rats, Transgenic
D053245:RANK Ligand