Cyclosporin-A<i>in Vitro</i>Decreases Bone Resorption, Osteoclast Formation, and the Fusion of Cells of the Monocyte-Macrophage Lineage

Orcel, Philippe; Denne, M A; Vernejoul, M. C. De

doi:10.1210/endo-128-3-1638

Cited by 80 publications

(34 citation statements)

References 35 publications

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“…Administration of CsA to laboratory animals also produces conflicting results ranging from increased bone formation to severe osteopenia [10,11]. It is not completely understood why CsA treatment would elicit opposing effects, but it is possible that these differences in results are due to the use of different species, genders, ages, and most importantly, different drug concentrations and duration of administration in these studies [10,11,[47][48][49].…”

Section: Discussionmentioning

confidence: 99%

Cyclosporin A elicits dose-dependent biphasic effects on osteoblast differentiation and bone formation

Yeo

Beck

McDonald

et al. 2007

Bone

111

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Cyclosporin A (CsA) is thought to prevent immune reactions after organ transplantation by inhibiting calcineurin (Cn) and its substrate, the Nuclear Factor of Activated T cells (NFAT). A dichotomy exists in describing the effects of CsA on bone formation. The concept that the suppression of Cn/ NFAT signaling by CsA inhibits bone formation is not entirely supported by many clinical reports and laboratory animal studies. Gender, dosage and basal inflammatory activity have all been suggested as explanations for these seemingly contradictory reports. Here we examine the effects of varying concentrations of CsA on bone formation and osteoblast differentiation and elucidate the role of NFATc1 in this response. We show that low concentrations of CsA (<1μM in vitro and 35.5 nM in vivo) are anabolic as they increase bone formation, osteoblast differentiation, and bone mass, while high concentrations (>1μM in vitro and in vivo) elicit an opposite and catabolic response. The overexpression of constitutively-active NFATc1 inhibits osteoblast differentiation, and treatment with low concentrations of CsA does not ameliorate this inhibition. Treating osteoblasts with low concentrations of CsA (<1μM) increases fra-2 gene expression and protein levels in a dose-dependent manner as well as AP-1 DNA binding activity. Finally, NFATc1 silencing with siRNA increases Fra-2 expression, whereas NFATc1 overexpression inhibits Fra-2 expression. Therefore, NFATc1 negatively regulates osteoblast differentiation, and its specific inhibition may represent a viable anabolic therapy for osteoporosis.

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Section: Discussionmentioning

confidence: 99%

Cyclosporin A elicits dose-dependent biphasic effects on osteoblast differentiation and bone formation

Yeo

Beck

McDonald

et al. 2007

Bone

111

View full text Add to dashboard Cite

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“…In an early report using limb bones cultured from fetal rats, CsA did not initially alter bone resorption, but decreased bone resorption after several days in culture, a finding attributed to its inhibition of osteoclast formation (Orcel et al 1991). A more compelling connection between calcineurin and osteoclast differentiation has been made in a bone marrow culture model, in which either CsA or FK506 caused a concentration-dependent inhibition of differentiation of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (Takayanagi et al 2002).…”

Section: Osteoclast Differentiationmentioning

confidence: 99%

Transcriptional regulation by calcium, calcineurin, and NFAT

Hogan¹,

Chen²,

Nardone³

et al. 2003

Genes Dev.

1,750

1,795

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“…Patients after allogeneic BMT are also exposed to numerous factors that can affect bone mineral metabolism: induction and consolidation therapies, bed rest, 5,6 conditioning regimen for BMT, steroids, 7 CsA therapy 8,9 and GVHD. 10 In female patients disturbance of gonadal function causes chronic estrogen deficiency 11 with an increased risk for osteoporosis.…”

mentioning

confidence: 99%

Bone mineral density after allogeneic bone marrow transplantation

Kauppila

Irjala²,

Koskinen³

et al. 1999

Bone Marrow Transplant

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Summary:Bone turnover markers and bone mineral density (BMD) were studied in 25 adult patients (14 females, 11 males) who had undergone allogeneic bone marrow transplantation (BMT). The interval from BMT to the first examination was at least 1 year (mean 3, range 1-10). Mean age of the patients at the time of first evaluation was 42 (range 19-54) years. Blood samples and urine collections for evaluation of biochemical factors reflecting skeletal turnover were performed together with the first BMD measurement. BMD was measured from the lumbar vertebrae (L2 to L4) with computed tomography and results were expressed as Z-scores. At the time of the first measurement five patients (20%) had Z-scores Ͻ−2.5 s.d. and 12 patients (48%) between −1 and −2.5 s.d. In 12 patients BMD assessments were repeated and it seemed that reduction in BMD had mostly occurred during and shortly after BMT and remained the same during follow-up. The cross-linked carboxyterminal telopeptide of type I collagen (ICTP) correlated negatively with BMD (r = −0.45, P = 0.045) as did bone-specific alkaline phosphatase (BAP; r = −0.64, P = 0.002). No correlation between BMD and time interval from diagnosis to BMT, conditioning regimen, corticosteroid use or hospital stay during transplantation was found. In conclusion, bone disease is common after BMT. Our findings demonstrate an increased collagen and bone turnover and a high risk of osteoporosis. BMD measurements must be repeated regularly and collagen markers such as ICTP and BAP can be beneficial in estimating the activity of bone disease. Keywords: allogeneic bone marrow transplantation; ICTP; bone-specific alkaline phosphatase; bone mineral density; osteoporosis Transplant recipients are at risk of osteoporosis. Muchmore et al 1 reported low mean density of vertebral bone in heart transplant patients. Bone loss takes place mostly during the initial year after transplantation. 2 Rapid loss of vertebral mineral density has also been reported after renal transplantation, with most of the loss occurring within the first 6 months. after. Bone loss was related to number of hospital days but not to any other factor.Patients after allogeneic BMT are also exposed to numerous factors that can affect bone mineral metabolism: induction and consolidation therapies, bed rest, 5,6 conditioning regimen for BMT, steroids, 7 CsA therapy 8,9 and GVHD. 10 In female patients disturbance of gonadal function causes chronic estrogen deficiency 11 with an increased risk for osteoporosis. Carlson et al 12 studied the effect of myeloablative therapy on bone metabolism during the first 3 months after transplantation and found significant changes in serum markers of bone metabolism, which implied a net loss of bone over the study period. In 1997 Keilholz et al 13 reported normal BMDs after ABMT with a median interval of 5 years from autografting.The purpose of the present study was to evaluate the occurrence of bone disease after BMT by measuring BMD and biochemical markers of bone metabolism. Patients and methodsWe exami...

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Cyclosporin-Ain VitroDecreases Bone Resorption, Osteoclast Formation, and the Fusion of Cells of the Monocyte-Macrophage Lineage

Cited by 80 publications

References 35 publications

Cyclosporin A elicits dose-dependent biphasic effects on osteoblast differentiation and bone formation

Cyclosporin A elicits dose-dependent biphasic effects on osteoblast differentiation and bone formation

Transcriptional regulation by calcium, calcineurin, and NFAT

Bone mineral density after allogeneic bone marrow transplantation

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