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Statin blocks negative impact of PIs on bone formation in vitro

<p>Mark Mascolini</p>


December 10, 2011

Ritonavir-boosted or unboosted atazanavir or lopinavir promoted stem cell changes that could lead to decreased bone formation, according to results of cell studies by Jacqueline Capeau and colleagues at Saint-Antoine Hospital in Paris. Exposing the cells to pravastatin blocked these protease inhibitor (PI)-induced changes. [1]

Bone density declines with HIV infection, and that decline can accelerate with antiretroviral therapy. Treatment with certain PIs or tenofovir heightened the risk of osteopenia and osteoporosis in longitudinal studies. SMART trial participants randomised to take antiretrovirals continuously had more bone loss than those randomised to CD4-based treatment interruptions. [2]

Indinavir and nelfinavir – two PIs rarely used today – resulted in poorly functioning osteoblasts, the cells responsible for new bone formation. Capeau and coworkers planned a series of cell studies to see if two currently prescribed antiretrovirals, lopinavir and atazanavir with or without ritonavir, affect cell properties that could promote bone loss in people with HIV.

The researchers used menenchymal bone marrow stem cells from young, healthy donors. They passaged these stem cells every 5 days to simulate ageing. For up to 40 days, they exposed the cells to doses of lopinavir, atazanavir, and ritonavir equivalent to maximum concentrations of those PIs typically attained in people taking them at prescribed doses.

Stem-cell numbers dropped sharply after 10 to 15 days of lopinavir (with or without ritonavir) and after 20 to 25 days of atazanavir (with or without ritonavir). The PIs had no effect on cell survival, a finding suggesting that decreased proliferative capacity accounted for these declines in stem cell number.

Assessing stem-cell senescence by measuring senescence-associated beta-galactosidase activity, the researchers found that both atazanavir and lopinavir significantly induced premature senescence. Increased reactive oxygen species (ROS) production in these cells suggested that oxidative stress may be responsible for cell ageing. Atazanavir and lopinavir also raised levels of superoxide dismutase, an antioxidant enzyme, in these cells. Both PIs increased expression of the cell-cycle inhibitors P16 and P21. Finally, the two PIs induced accumulation of prelamin A, a cell-ageing marker associated with cell senescence.

Mesenchymal stem cells normally differentiate into an even balance of osteoblasts and adipocytes (fat cells). With ageing, differentiation to adipocytes begins to outweigh differentiation to osteoblasts. Age-related bone loss is marked by increased bone marrow fat, which leads to decreased bone formation.

Stem cells pretreated with lopinavir or atazanavir lost their ability to differentiate into osteoblasts, a result Capeau suggested could mean these PIs irreversibly affect the menenchymal stem cell pool in bone marrow. Lopinavir-exposed stem cells also failed to differentiate into adipocytes, while atazanavir-exposed cells promoted increased differentiation into adipocytes. The investigators proposed that atazanavir could lower the number of osteoblasts in treated people by upsetting the balance between adipocytes and osteoblasts in bone marrow.

When Capeau and colleagues exposed stem cells to pravastatin and the study PIs, they found that this statin prevented PI-induced senescence, reduced oxidative stress, and restored the differentiation of stem cells to an even balance of osteoblasts and adipocytes.

The researchers concluded that their cell-study data “show that some PIs can alter osteoblast formation by a direct effect on osteoblast differentiation and also by inducing premature senescence of the bone marrow progenitors.”

References

  1. Hernandez-Vallejo S et al. Some HIV protease inhibitors induce premature senescence and alter osteoblastic cell fate determination of human bone marrow mesenchymal stem cells. 2nd International Workshop on HIV and Aging. October 27-28, 2011. Baltimore, Maryland. Abstract: O_14.
  2. Grund B et al for the INSIGHT SMART Body Composition Substudy Group. Continuous antiretroviral therapy decreases bone mineral density. AIDS. 2009 July 31; 23(12): 1519–1529. doi:  10.1097/QAD.0b013e32832c1792.

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