Alendronate prevents cyclosporin A-induced osteopenia in the rat

Sass, David A.; Bowman, Andrew R.; Yuan, Z.; Ma, Yanfei; Jee, W.S.S.; Epstein, Sol

doi:10.1016/s8756-3282(97)00071-9

Cited by 61 publications

(35 citation statements)

References 33 publications

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“…With such specificity, one would expect that the skeletal effects of calcineurin inhibition by FK506 and calcineurin gene deletion are identical. In other words, reduced osteoblast differentiation and bone formation should be the mechanism through which calcineurin inhibitors cause bone loss (18)(19)(20)(21). Although this may be the case, the osteoporosis resulting from calcineurin inhibitors is characterized by a high-turnover state in which both bone resorption and through-coupling bone formation are elevated (18,19).…”

Section: Discussionmentioning

confidence: 99%

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Calcineurin regulates bone formation by the osteoblast

Sun

Blair

Peng

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

146

108

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Two of the most commonly used immunosuppressants, cyclosporine A and tacrolimus (FK506), inhibit the activity of a ubiquitously expressed Ca 2؉ ͞calmodulin-sensitive phosphatase, calcineurin. Because both drugs also cause profound bone loss in humans and in animal models, we explored whether calcineurin played a role in regulating skeletal remodeling. We found that osteoblasts contained mRNA and protein for all isoforms of calcineurin A and B. TAT-assisted transduction of fusion protein TAT-calcineurin A␣ into osteoblasts resulted in the enhanced expression of the osteoblast differentiation markers Runx-2, alkaline phosphatase, bone sialoprotein, and osteocalcin. This expression was associated with a dramatic enhancement of bone formation in intact calvarial cultures. Calcineurin A␣ ؊/؊ mice displayed severe osteoporosis, markedly reduced mineral apposition rates, and attenuated colony formation in 10-day ex vivo stromal cell cultures. The latter was associated with significant reductions in Runx2, bone sialoprotein, and osteocalcin expression, paralleled by similar decreases in response to FK506. Together, the gain-and loss-of-function experiments indicate that calcineurin regulates bone formation through an effect on osteoblast differentiation.FK506 ͉ osteoporosis ͉ runx-2

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Section: Discussionmentioning

confidence: 99%

“…The systemic administration of either drug to rats causes a dramatic osteoporosis (18,19). In humans, acute, rapid, severe bone loss ensues with a fracture incidence approaching 65% (20,21).…”

mentioning

confidence: 99%

Calcineurin regulates bone formation by the osteoblast

Sun

Blair

Peng

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

146

108

View full text Add to dashboard Cite

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“…Experimentally, cyclosporine first was shown to accelerate bone resorption in vivo using rats and to lead to a very severe high-turnover osteopenic state with increased levels of osteocalcin and calcitriol. Antiresorptive therapies, including estrogen, raloxifene, and bisphosphonates, attenuate the bone loss in this model, and this led to the hope that bisphosphonates would also prove effective in the clinical arena (58,59). Testosterone did not retard the changes significantly (59).…”

Section: Effects Of Immune Suppressive Therapiesmentioning

confidence: 99%

“…Antiresorptive therapies, including estrogen, raloxifene, and bisphosphonates, attenuate the bone loss in this model, and this led to the hope that bisphosphonates would also prove effective in the clinical arena (58,59). Testosterone did not retard the changes significantly (59). Effects of tacrolimus in the same rat model are broadly similar to those of cyclosporine (60).…”

Section: Effects Of Immune Suppressive Therapiesmentioning

confidence: 99%

“…Studies by the same group, also conducted in rats, have shown that cyclosporine, but not tacrolimus, lowered testosterone in male animals, whereas both led to similar highturnover osteopenia. Testosterone replacement failed to prevent this bone loss (59). Sirolimus, therefore, seems to be more benign than are cyclosporine and tacrolimus, at least in experimental settings (68), and in the clinical arena, there also is some evidence that abnormally high bone turnover is less likely during treatment with sirolimus than with cyclosporine (69).…”

Section: Effects Of Immune Suppressive Therapiesmentioning

confidence: 99%

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Pathogenesis and Prevention of Bone Loss in Patients Who Have Kidney Disease and Receive Long-Term Immunosuppression

Cunningham¹

2007

Journal of the American Society of Nephrology

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The coexistence of kidney disease with a need for immunosuppressive therapy leads to the convergence of several threats to bone. These comprise general effects of the primary disease, e.g., inflammatory state, more specific effects of acute renal failure or chronic kidney disease, and effects of therapies. Multisystem inflammatory disease that requires immunosuppression is associated frequently with kidney damage, and any reduction of kidney function that takes the patient into or beyond chronic kidney disease stage 2 for more than a short time is likely to have a negative impact on bone health. Bone mineral density frequently is low and fracture rates are high, although correlations often are poor. Chronic inflammation leads to local and systemic imbalance between bone formation and resorption. Upregulation of NF-␤ ligand (RANKL) and variable downregulation of osteoprotegerin are implicated, and bone health may improve in response to treatment of the inflammatory state. Certain immunosuppressive agents, especially glucocorticoids and calcineurin inhibitors, contribute further to bone loss. Antiresorptive agents such as bisphosphonates are used widely and, although able to prevent loss of bone mineral density, have uncertain effects on fracture rates. Augmentation of anabolic activity is desirable but elusive. Synthetic parathyroid hormone is untested but has potential. Manipulation of the RANKL/osteoprotegerin system now is feasible using antibodies to RANKL or synthetic osteoprotegerin. In the future, manipulation of the calcium-sensing receptor using calcimimetic or calcilytic agents may allow the anabolic effects of parathyroid hormone to be harnessed to good effect. With all of these therapies, it will be important to assess response in relation to important clinical end points such as fracture.

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A novel quercetin analogue from a medicinal plant promotes peak bone mass achievement and bone healing after injury and exerts an anabolic effect on osteoporotic bone: The role of aryl hydrocarbon receptor as a mediator of osteogenic action

Sharan

Mishra

Swarnkar

et al. 2011

Journal of Bone and Mineral Research

100

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We recently reported that extracts made from the stem bark of Ulmus wallichiana promoted peak bone mass achievement in growing rats and preserved trabecular bone mass and cortical bone strength in ovariectomized (OVX) rats. Further, 6-C-b-D-glucopyranosyl-(2S,3S)-(þ)-3',4',5,7-tetrahydroxyflavanol (GTDF), a novel flavonol-C-glucoside isolated from the extracts, had a nonestrogenic bonesparing effect on OVX rats. Here we studied the effects of GTDF on osteoblast function and its mode of action and in vivo osteogenic effect. GTDF stimulated osteoblast proliferation, survival, and differentiation but had no effect on osteoclastic or adipocytic differentiation. In cultured osteoblasts, GTDF transactivated the aryl hydrocarbon receptor (AhR). Activation of AhR mediated the stimulatory effect of GTDF on osteoblast proliferation and differentiation. Furthermore, GTDF stimulated cAMP production, which mediated osteogenic gene expression. GTDF treatments given to 1-to 2-day-old rats or adult rats increased the mRNA levels of AhR target genes in calvaria or bone marrow stromal cells. In growing female rats, GTDF promoted parameters of peak bone accrual in the appendicular skeleton, including increased longitudinal growth, bone mineral density, bone-formation rate (BFR), cortical deposition, and bone strength. GTDF promoted the process of providing newly generated bone to fill drill holes in the femurs of both estrogen-sufficient and -deficient rats. In osteopenic OVX rats, GTDF increased BFR and significantly restored trabecular bone compared with the ovaries-intact group. Together our data suggest that GTDF stimulates osteoblast growth and differentiation via the AhR and promotes modeling-directed bone accrual, accelerates bone healing after injury, and exerts anabolic effects on osteopenic rats likely by a direct stimulatory effect on osteoprogenitors. Based on these preclinical data, clinical evaluation of GTDF as a potential bone anabolic agent is warranted. ß

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Alendronate prevents cyclosporin A-induced osteopenia in the rat

Cited by 61 publications

References 33 publications

Calcineurin regulates bone formation by the osteoblast

Calcineurin regulates bone formation by the osteoblast

Pathogenesis and Prevention of Bone Loss in Patients Who Have Kidney Disease and Receive Long-Term Immunosuppression

A novel quercetin analogue from a medicinal plant promotes peak bone mass achievement and bone healing after injury and exerts an anabolic effect on osteoporotic bone: The role of aryl hydrocarbon receptor as a mediator of osteogenic action

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