Intermittent treatment with parathyroid hormone (PTH) as well as a non-peptide small molecule agonist of the PTH1 receptor inhibits adipocyte differentiation in human bone marrow stromal cells

Rickard, David J.; Wang, Feilan; Rodriguez-Rojas, Ana-Maria; Wu, Zining; Trice, Wen J.; Hoffman, Sandra J.; Votta, Bartholomew J.; Stroup, George B.; Kumar, Sanjay; Nuttall, Mark

doi:10.1016/j.bone.2006.06.010

Cited by 138 publications

(103 citation statements)

References 47 publications

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“…(1,3) An effective bone anabolic agent would induce bone formation by stimulating osteoblast activity, by protecting osteoblasts against premature death, and by promoting the differentiation of MSC down the osteoblast rather than the adipocyte lineage. (1) In fact, several studies have demonstrated that it is possible to stimulate osteoblast differentiation at the expense of adipogenesis using compounds such as parathyroid hormone, (18) interferon gamma, (19,20) and strontium ranelate. (21) The active metabolite of vitamin D, 1,25(OH) 2 D 3 , has also been shown to stimulate bone formation by promoting osteoblastogenesis (12) and inhibiting adipogenesis (17) in a murine model of age-related bone loss.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological inhibition of PPARγ increases osteoblastogenesis and bone mass in male C57BL/6 mice

Duque

Vidal

et al. 2012

Journal of Bone and Mineral Research

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Infiltration of bone marrow with fat is a prevalent feature in people with age-related bone loss and osteoporosis, which correlates inversely with bone formation and positively with high expression levels of peroxisomal proliferator-activated receptor gamma (PPARg). Inhibition of PPARg thus represents a potential therapeutic approach for age-related bone loss. In this study, we examined the effect of PPARg inhibition on bone in skeletally mature C57BL/6 male mice. Nine-month-old mice were treated with a PPARg antagonist, bisphenol-A-diglycidyl ether (BADGE), alone or in combination with active vitamin D (1,25[OH] 2 D 3 ) for 6 weeks. Micro-computed tomography and bone histomorphometry indicated that mice treated with either BADGE or BADGE þ 1,25(OH) 2 D 3 had significantly increased bone volume and improved bone quality compared with vehicle-treated mice. This phenotype occurred in the absence of alterations in osteoclast number. Furthermore, the BADGE þ 1,25(OH) 2 D 3 -treated mice exhibited higher levels of unmineralized osteoid. All of the treated groups showed a significant increase in circulating levels of bone formation markers without changes in bone resorption markers, while blood glucose, parathyroid hormone, and Ca þ remained normal. Furthermore, treatment with BADGE induced higher levels of expression of vitamin D receptor within the bone marrow. Overall, treated mice showed higher levels of osteoblastogenesis and bone formation concomitant with decreased marrow adiposity and ex vivo adipogenesis. Taken together, these observations demonstrate that pharmacological inhibition of PPARg may represent an effective anabolic therapy for osteoporosis in the near future. ß

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Section: Discussionmentioning

confidence: 99%

Pharmacological inhibition of PPARγ increases osteoblastogenesis and bone mass in male C57BL/6 mice

Duque

Vidal

et al. 2012

Journal of Bone and Mineral Research

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“…Also, the only way to ensure that in vitro responses to PTH are relevant to the in vivo effects caused by transient exposure to injected PTH is to study short term effects of the hormone, or to expose cells to the hormone for a few hours per day during longer term studies. This is because, unlike the in vivo situation, PTH is not substantially degraded after addition to cultured osteoblastic cells, and remains fully active for at least 72 hours [12,50]. Although PTHR1 is desensitized and internalized within minutes after addition of PTH, this phenomenon does not model the effects of transient exposure to the hormone.…”

Section: How Does Intermittent Pth Increase Osteoblast Number?mentioning

confidence: 96%

“…In vitro studies have shown that activation of the PTH receptor in pre-adipocytic cells with PTHrP caused phosphorylation of PPARγ and inhibition of its transactivation activity [75]. Further, culture of human mesenchymal stem cells with PTH for 1 hour per day prevented the ability of a cocktail of dexamethasone, insulin, isobutyl-methylxanthine and troglitazone to stimulate the development of adipocytes; and this inhibitory effect of the hormone was mediated by cAMP-activated PKA [50]. Interestingly, PTH inhibition of adipogenesis was not seen when cells were maintained in the continuous presence of PTH in this study.…”

Section: Attenuation Of Adipogenesismentioning

confidence: 99%

Molecular and cellular mechanisms of the anabolic effect of intermittent PTH

Jilka

2007

Bone

623

531

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Intermittent administration of parathyroid hormone (PTH) stimulates bone formation by increasing osteoblast number, but the molecular and cellular mechanisms underlying this effect are not completely understood. In vitro and in vivo studies have shown that PTH directly activates survival signaling in osteoblasts; and that delay of osteoblast apoptosis is a major contributor to the increased osteoblast number, at least in mice. This effect requires Runx2-dependent expression of antiapoptotic genes like Bcl-2. PTH also causes exit of replicating progenitors from the cell cycle by decreasing expression of cyclin D and increasing expression of several cyclin-dependent kinase inhibitors. Exit from the cell cycle may set the stage for pro-differentiating and pro-survival effects of locally produced growth factors and cytokines, the level and/or activity of which are known to be influenced by PTH. Observations from genetically modified mice suggest that the anabolic effect of intermittent PTH requires insulin-like growth factor-I (IGF-I), fibroblast growth factor-2 (FGF-2), and perhaps Wnts. Attenuation of the negative effects of PPARγ may also lead to increased osteoblast number. Daily injections of PTH may add to the pro-differentiating and pro-survival effects of locally produced PTH related protein (PTHrP). As a result, osteoblast number increases beyond that needed to replace the bone removed by osteoclasts during bone remodeling. The pleiotropic effects of intermittent PTH, each of which alone may increase osteoblast number, may explain why this therapy reverses bone loss in most osteoporotic individuals regardless of the underlying pathophysiology.

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“…Interestingly, daily treatment with PTH has been shown to reverse both the decreased expression of osteogenic genes and the increased levels of adipogenic genes, namely peroxisome proliferator-activated receptor (PPAR)-γ and lipoprotein lipase (LPL), as shown in the femoral metaphysis of ovariectomized rats (Kulkarni et al, 2007). Moreover, a high PTH (1-34) dose (50 nM) added as a 1-h pulse, but not continuously, to human bone marrow mesenchymal cells was recently found to inhibit their adipogenic commitment (Rickard et al, 2006). These recent data thus suggest that the anabolic effect of PTH could be related at least in part to its capacity to inhibit the adipocytic program in the precursor cells for both osteoblasts and adipocytes.…”

Section: Introductionmentioning

confidence: 99%

The N- and C-terminal domains of parathyroid hormone-related protein affect differently the osteogenic and adipogenic potential of human mesenchymal stem cells

2010

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Intermittent treatment with parathyroid hormone (PTH) as well as a non-peptide small molecule agonist of the PTH1 receptor inhibits adipocyte differentiation in human bone marrow stromal cells

Cited by 138 publications

References 47 publications

Pharmacological inhibition of PPARγ increases osteoblastogenesis and bone mass in male C57BL/6 mice

Pharmacological inhibition of PPARγ increases osteoblastogenesis and bone mass in male C57BL/6 mice

Molecular and cellular mechanisms of the anabolic effect of intermittent PTH

The N- and C-terminal domains of parathyroid hormone-related protein affect differently the osteogenic and adipogenic potential of human mesenchymal stem cells

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