Background:  Loss of bone mineral density leading to osteopenia and, in some instances, osteoporosis complicated by bone fracture, occurs in one–third of HIV-1-seropositive individuals naïve to antiretroviral therapy (ART).  ART may accelerate development of such osteopenia in adults and children. Several lines of evidence suggest that hyperactivity of osteoclasts, the principle resorptive cell of bone, is primarily under control of the T-cell activation product TRANCE, and this cytokine is thus critical for pathophysiology of osteopenia. We hypothesized that the types of T-cell activation cytokines which predominate in HIV disease, and persist, or accelerate after ART, are critical to bone demineralization in these patients. We also postulated that a positive feedback could exist between HIV replication and TRANCE expression and protein production.

Methods: We compared TRANCE and TRANCE receptor(R) expression in PBMCs by RT-PCR and ELISA. We used cytochemical methods to determine osteoclastogenic activity. Cytokine levels in plasma and p24 Gag levels was measured by ELISA. Analysis was done by pairing t-test for the means.

Results: TRANCE mRNA and protein were overproduced in PBMCs of 9 of the 12 HIV+ individuals compared to controls (p<0.015). In parallel with  the in vivo findings, HIV-1 infection of PHA-activated control PBMCs  led to marked elevation of TRANCE  expression  and TRANCE protein production (p<0.001) in  3 different  donors, independent of HIV replication. Exposure of resting PBMCs to levels of recombinant    gp120 comparable to that detectable in vivo resulted in marked TRANCE mRNA induction. Osteoclastic precursor cells cultured with supernatants from PBMCs infected with HIV led to a 2.2-fold increase over control supernatants (p<0.003) in the number of functional osteoclasts.  Mean levels of OPG in plasma were increased in the 12 HIV+ subjects vs control (p<0.005) similar to the reciprocal increase in this decoy receptor seen in other states of TRANCE mediated osteopenia. Finally we sought to explore why ART appears to increase osteopenia in the setting of HIV.  Other groups have shown that  suppression of viral load by ART  lead to increase in  activated T cells and  their  expression of TNF-α  and TNFRII. Significantly greater levels of TNF-α or TNFRII were noted in our HIV+ donors (p<0.001 for TNF-α and p<0.02 for TNFRII). These levels of TNF-α are comparable to those which synergize with low levels TRANCE in osteoclast activation in vitro. We therefore assessed whether TRANCE and TNF-α might also be synergistic in terms of HIV-1 replication. An additive effect was seen up to 500 pg/mL TNF-α, higher levels were markedly synergistic with TRANCE in induction of viral replication. 

Conclusions: Together these studies suggests a mechanism by which HIV-1 or its envelop gp120 can promote osteoclastogenesis  and bone demineralization via induction of TRANCE , as well as TRANCE- TNF-α synergy.