Effects of age on parathyroid hormone signaling in human marrow stromal cells

Zhou, Shuanhu; Bueno, Ericka M.; Kim, Sung Won; Amato, Ilaria; Shen, Longxiang; Hahne, Jochen; Bleiberg, Ilan; Morley, Paul; Glowacki, Julie

doi:10.1111/j.1474-9726.2011.00717.x

Cited by 24 publications

(34 citation statements)

References 72 publications

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“…Thus, we tested whether PTH regulates CYP27B1 in hMSCs. Detecting lower expression of PTHR1 in hMSCs from older than younger subjects in this series is consistent with our previous report of age-related declines in PTHR1 expression and signaling with 10 nM PTH1-34 (Zhou et al 2011). In this project, however, a higher concentration (100 nM) of PTH1-34 was used and was shown to be effective in upregulating CYP27B1 in cells from elders.…”

Section: Discussionsupporting

confidence: 93%

“…We used two experimental approaches to determine the role(s) of CREB in PTH upregulation of CYP27B1 in hMSCs: targeted CREB silencing and use of small molecule inhibitor of CREB signaling. In a previous analysis of the age-related decline in PTH signaling in hMSCs, we showed that CREB-siRNA completely obliterated PTH stimulation of osteoblast differentiation that was typical for hMSCs from young subjects (Zhou et al 2011). On the other hand, in this study with hMSCs from older subjects, transfection with CREB-siRNA blocked PTH1-34 upregulation of CYP27B1 at both 2 hours and 8 hours.…”

Section: Discussionmentioning

confidence: 83%

“…In vivo and in vitro evidence indicates that PTH induces IGF-I (Canalis et al 1989; Pfeilschifter et al 1995; Watson et al 1995; Shinoda et al 2010). We determined that PTH peptides upregulated both IGF-I and IGF-II in hMSCs (Zhou et al 2011) and that rhIGF-I induced CYP27B1 expression and 1α-hydroxylase activity in hMSCs (Zhou et al 2010). Recently, Jilka et al showed that PTH has greater bone anabolic effects in older mice because in addition to its stimulation of bone formation, it antagonized the age-associated increase in oxidative stress and adverse effects on birth and survival of osteoblasts (Jilka et al 2010).…”

Section: Introductionmentioning

confidence: 99%

“…Further, PTH in vitro (50 nM) protected osteoblasts from acute oxidative-stress-related effects. We recently demonstrated by genetic and pharmacological means that some effects of age on hMSCs were reproduced by experimental blocking of PTH signaling (Zhou et al 2011). In addition, PTH is the major stimulus for renal production of 1,25(OH) 2 D 3 (Haussler et al 1976; Brenza et al 1998; Brenza & DeLuca 2000).…”

Section: Introductionmentioning

confidence: 99%

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Age‐related decline in osteoblastogenesis and 1α‐hydroxylase/CYP27B1 in human mesenchymal stem cells: stimulation by parathyroid hormone

2011

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Summary With aging, there is a decline in bone mass and in osteoblast differentiation of human mesenchymal stem cells (hMSCs) in vitro. Osteoblastogenesis can be stimulated with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and, in some hMSCs, by the precursor 25-hydroxyvitamin D3 (25OHD3). CYP27B1/1α-hydroxylase activates 25OHD3 and, to a variable degree, hMSCs express CYP27B1. In this study, we tested the hypotheses 1) that age affects responsiveness to 25OHD3 and expression/activity of CYP27B1 in hMSCs, and 2) that parathyroid hormone (PTH) upregulates CYP27B1 in hMSCs, as it does in renal cells. There were age-related declines in osteoblastogenesis (n=8, p=0.0286) and in CYP27B1 gene expression (n=27, r=−0.498; p=0.008) in hMSCs. Unlike hMSCs from young subjects (≤ 50-years), hMSCs from older subjects (≥ 55-years) were resistant to 25OHD3 stimulation of osteoblastogenesis. PTH1-34 (100 nM) provided hMSCs with responsiveness to 25OHD3 (p=0.0313, Wilcoxon matched pairs test) and with two episodes of increased 1,25(OH)2D3 synthesis, of CREB activation, and of CYP27B1 upregulation. Both increases in CYP27B1 expression by PTH were obliterated by CREB-siRNA or KG-501 (which specifically inhibits the downstream binding of activated CREB). Only the second period of CREB signaling was diminished by AG1024, an inhibitor of insulin-like growth factor-I receptor kinase. Thus, PTH stimulated hMSCs from elders with responsiveness to 25OHD3 by upregulating expression/activity of CYP27B1 and did so through CREB and IGF-I pathways.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Age‐related decline in osteoblastogenesis and 1α‐hydroxylase/CYP27B1 in human mesenchymal stem cells: stimulation by parathyroid hormone

2011

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“…38 A growing body of evidence suggests that this deficit in mechanotransduction is due to a compromised ability of cells from aged individuals to interpret and respond to anabolic signaling. 14,58 Thus, developing interventions that overcome these deficits will be important in implementing exercise-based strategies for the treatment of bone loss with age.…”

Section: Introductionmentioning

confidence: 99%

Enhancement of Flow-Induced AP-1 Gene Expression by Cyclosporin A Requires NFAT-Independent Signaling in Bone Cells

et al. 2014

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Growing evidence suggests that aging compromises the ability of the skeleton to respond to anabolic mechanical stimuli. Recently, we reported that treating senescent mice with Cyclosporin A (CsA) rescued aging-related deficits in loading-induced bone formation. Given that the actions of CsA are often attributed to inhibition of the calcineurin/NFAT axis, we hypothesized that CsA enhances gene expression in bone cells exposed to fluid flow, by inhibiting nuclear NFATc1 accumulation. When exposed to flow, MC3T3-E1 osteoblastic cells exhibited rapid nuclear accumulation of NFATc1 that was abolished by CsA treatment. Under differentiation conditions, intermittent CsA treatment enhanced gene expression of late osteoblastic differentiation markers and activator protein 1 (AP-1) family members. Superimposing flow upon CsA further enhanced expression of the AP-1 members Fra-1 and c-Jun. To delineate the contribution of NFAT in this response, cells were treated with VIVIT, a specific inhibitor of the calcineurin/NFAT interaction. Treatment with VIVIT blocked flow-induced nuclear NFATc1 accumulation but did not recapitulate the CsA-mediated enhancement of flow-induced AP-1 component gene expression. Taken together, our study is the first to demonstrate that CsA enhances mechanically-induced gene expression of AP-1 components in bone cells, and suggests that this response requires calcineurin-dependent mechanisms that are independent of inhibiting NFATc1 nuclear accumulation.

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Clinical characteristics influence in vitro action of 1,25-dihydroxyvitamin D3 in human marrow stromal cells

Zhou

Glowacki

Kim

et al. 2012

Journal of Bone and Mineral Research

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Vitamin D is important for bone health, with low vitamin D levels being associated with skeletal fragility and fractures. Among its other biological activities, 1,25-dihydroxyvitamin D (1,25(OH)2D), stimulates the in vitro differentiation of human marrow stromal cells (hMSCs) to osteoblasts, which can be monitored by increases in Alkaline Phosphatase enzyme activity or osteocalcin gene expression. In this study, we tested the hypotheses that age and clinical attributes of subjects influence in vitro responsiveness of hMSCs to 1,25(OH)2D3. In a cohort of subjects whose hMSCs were isolated from bone marrow discarded during hip replacement surgery for osteoarthritis, there were significant inverse correlations with age for bone mineral density, renal function, body mass index, fat mass index, and lean mass index (n=36–53). There were significant correlations with serum 25(OH)D for serum PTH, body mass index, fat mass index, and lean mass index (n=47–50). In vivo-in vitro correlation analyses indicated that there were significantly greater in vitro effects of 1,25(OH)2D3 to stimulate osteoblast differentiation in hMSCs obtained from subjects who were younger than 65 years of age, or who had serum 25(OH)D ≤20 ng/mL, elevated serum PTH, or better renal function, assessed by estimated glomerular filtration rate. The greater in vitro stimulation of osteoblast differentiation by 1,25(OH)2D3 in hMSCs from vitamin D-deficient subjects suggests that vitamin D repletion may lead to more vigorous bone formation in subjects at risk.

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Effects of age on parathyroid hormone signaling in human marrow stromal cells

Cited by 24 publications

References 72 publications

Age‐related decline in osteoblastogenesis and 1α‐hydroxylase/CYP27B1 in human mesenchymal stem cells: stimulation by parathyroid hormone

Age‐related decline in osteoblastogenesis and 1α‐hydroxylase/CYP27B1 in human mesenchymal stem cells: stimulation by parathyroid hormone

Enhancement of Flow-Induced AP-1 Gene Expression by Cyclosporin A Requires NFAT-Independent Signaling in Bone Cells

Clinical characteristics influence in vitro action of 1,25-dihydroxyvitamin D3 in human marrow stromal cells

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