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HIV protease inhibitors selectively induce gene expression alterations associated with reduced calcium deposition in

Andrea P Malizia1, Eoin Cotter, Nicholas Chew

  • 1General Clinical Research Unit, Mater Misericordiae University Hospital, School of Medicine and Medical Sciences, University College Dublin, 44 Eccles Street, Dublin 7, Ireland.

AIDS Research and Human Retroviruses
|March 3, 2007
PubMed

Insights

Protease inhibitors (PIs) used to treat HIV-1 can harm bone health. This study found that nelfinavir and indinavir alter osteoblast gene expression, potentially explaining reduced bone formation and identifying TIMP-3 as a key factor.

Area of Science:

  • Bone biology
  • Virology
  • Pharmacology

Background:

  • HIV-infected patients exhibit reduced bone mineral density.
  • Antiretroviral therapy, particularly protease inhibitors (PIs), is suspected to contribute to bone loss.

Purpose of the Study:

  • To investigate the effects of PIs on human osteoblast gene expression.
  • To identify specific genes involved in PI-induced inhibition of bone formation.

Main Methods:

  • Exposure of primary human osteoblasts to various PIs (NFV, IDV, SQV, RTV).
  • Analysis of gene expression using gene-chip microarrays.
  • Assessment of osteoblast function markers (Runx-2 mRNA, calcium deposition, ALP activity).
  • Validation using siRNA to silence TIMP-3 expression.

Main Results:

  • NFV and IDV significantly decreased Runx-2 mRNA, calcium deposition, and ALP activity.
  • PI exposure induced widespread gene expression changes.
  • A specific set of 21 genes (8 upregulated, 13 downregulated) were altered by NFV and IDV.
  • TIMP-3 was identified among the altered genes; silencing it rescued osteoblast function.

Conclusions:

  • NFV and IDV treatment are linked to a reduced osteoblastic phenotype.
  • A group of 21 dysregulated genes, including TIMP-3, may mediate PI-induced inhibition of osteoblast function.
  • TIMP-3 plays a significant role in PI-induced osteoblast dysfunction.

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