Tenofovir treatment of primary osteoblasts alters gene expression profiles: Implications for bone mineral density loss

Grigsby, Iwen F.; Pham, Lan; Mansky, Louis M.; Gopal, Raj K.; Carlson, Ann E.; Mansky, Kim C.

doi:10.1016/j.bbrc.2010.02.080

Cited by 71 publications

(57 citation statements)

References 26 publications

(23 reference statements)

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“…Indeed, assuming that OC is a marker which a) is secreted solely by osteoblasts, b) is proosteoblastic and c) whose alterations induce pathologic alterations in BMD [9], it can be reasonably speculated that the detrimental effects of TDF on bone metabolism might be driven mainly by OC-mediated loss of osteoblast function. Accordingly, our results provide for the first time in vivo indirect evidence that the effect of TDF on osteoblast activity is concentration-dependent, as previously documented in vitro in osteoblast cultures [10].…”

Section: P=074 In Patients With Altered Vs Normal Ctx Values)supporting

confidence: 85%

Determinants of bone diseases in tenofovir-treated HIV patients

Gervasoni

Minisci

Meraviglia

et al. 2016

Aids

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Section: P=074 In Patients With Altered Vs Normal Ctx Values)supporting

confidence: 85%

Determinants of bone diseases in tenofovir-treated HIV patients

Gervasoni

Minisci

Meraviglia

et al. 2016

Aids

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“…Tenofovir, which has also been associated with BMD loss in the setting of HIV, but possibly acts via renally-mediated phosphate loss and effects on the osteoblast rather than the OC [21], had no impact on Wnt5 when added alone, and led to a decrease in Wnt5 protein in RANKL treated cultures (Fig. 1, p<0.03).…”

Section: Resultsmentioning

confidence: 99%

Noncanonical Wnt signaling promotes osteoclast differentiation and is facilitated by the human immunodeficiency virus protease inhibitor ritonavir

Santiago

Oguma

Brown

et al. 2012

Biochemical and Biophysical Research Communications

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Wnt proteins that signal via the canonical Wnt/β-catenin pathway directly regulate osteoblast differentiation. In contrast, most studies of Wnt-related effects on osteoclasts involve indirect changes. While investigating bone mineral density loss in the setting of human immunodeficiency virus (HIV) infection and its treatment with the protease inhibitor ritonavir (RTV), we observed that RTV decreased nuclear localization of β-catenin, critical to canonical Wnt signaling, in primary human and murine osteoclast precursors. This occurred in parallel with upregulation of Wnt5a and Wnt5b transcripts. These Wnts typically stimulate noncanonical Wnt signaling, and this can antagonize the canonical Wnt pathway in many cell types, dependent upon Wnt receptor usage. We now document RTV-mediated upregulation of Wnt5a/b protein in osteoclast precursors. Recombinant Wnt5b and retrovirus-mediated expression of Wnt5a enhanced osteoclast differentiation from human and murine monocytic precursors, processes facilitated by RTV. In contrast, canonical Wnt signaling mediated by Wnt3a suppressed osteoclastogenesis. Both RTV and Wnt5b inhibited canonical, β-catenin/T cell factor-based Wnt reporter activation in osteoclast precursors. RTV- and Wnt5-induced osteoclast differentiation were dependent upon the receptor-like tyrosine kinase Ryk, suggesting that Ryk may act as a Wnt5a/b receptor in this context. This is the first demonstration of a direct role for Wnt signaling pathways and Ryk in regulation of osteoclast differentiation, and its modulation by a clinically important drug, ritonavir. These studies also reveal a potential role for noncanonical Wnt5a/b signaling in acceleration of bone mineral density loss in HIV-infected individuals, and illuminate a potential means of influencing such processes in disease states that involve enhanced osteoclast activity.

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“…In vitro studies have demonstrated altered expression of genes involved in cell signaling, energy and amino acid metabolism in osteoclasts and osteoblasts exposed to physiological doses of TFV (5, 6). TFV exposure resulted in abnormal calcium deposition in a study utilizing a sarcoma cell line (7).…”

Section: Potential Mechanisms Of Tenofovir Toxicity In Bonementioning

confidence: 99%

Tenofovir and bone health

Grant

Cotter

2016

Current Opinion in HIV and AIDS

113

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Purpose of review With continued improvements to the antiviral efficacy and tolerability of antiretroviral therapy (ART), long term safety of ART has become paramount. Low bone mineral density and fragility fractures are more common in HIV-infected individuals than in the general population. The aims of this review are to describe potential mechanisms underlying the adverse effects of tenofovir on bone, clinical studies of tenofovir disoproxil fumarate (TDF) and bone, and more recent bone data on tenofovir alafenamide (TAF). Recent finding Several studies have demonstrated an approximately 1–3% greater bone mineral density loss with TDF compared with other agents. Recent studies with TAF have shown improved bone (and renal) safety with similar virologic efficacy when compared to TDF. Summary Given these findings, TDF-containing regimens may be gradually replaced with non-TDF containing regimens for the treatment of HIV infection, especially in those at higher risk for fragility fracture.

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Tenofovir treatment of primary osteoblasts alters gene expression profiles: Implications for bone mineral density loss

Cited by 71 publications

References 26 publications

Determinants of bone diseases in tenofovir-treated HIV patients

Determinants of bone diseases in tenofovir-treated HIV patients

Noncanonical Wnt signaling promotes osteoclast differentiation and is facilitated by the human immunodeficiency virus protease inhibitor ritonavir

Tenofovir and bone health

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