Cardiotonic agent milrinone stimulates resorption in rodent bone organ culture.

Krieger, Nancy S.; Stappenbeck, Thad S.; Stern, Paula H.

doi:10.1172/jci112831

Cited by 19 publications

(6 citation statements)

References 19 publications

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“…In these studies, increased calcium and lysosomal enzyme release, as well as decreased bone calcium, Pi, and hydroxyproline content were found following thyroid hormone treatment. Furthermore, the slow de- velopment of bone resorption observed with T, in the current investigation was aligned closely with the delayed time courses of thyroid hormone-stimulated calcium release, which have been reported previously in fetal rat limb bones (7) and in neonatal mouse calvariae (9,11). Thyroid hormone action is thought to be initiated by the binding of iodothyronines to specific target cell nuclear receptors, and high affinity nuclear receptors for the thyroid hormones have been reported in osteosarcoma cells (36,37) and in neonatal mouse calvariae (10).…”

Section: Discussionsupporting

confidence: 91%

“…Prostaglandin's (especially those of the PGE series) are known to be potent stimulators of bone resorption (42), and the compounds are suggested to be important local mediators of bone resorption (13). However, unlike previous studies in neonatal mouse calvariae, which have shown inhibition of calcium release by indomethacin (8, 9,11) and increased PGE, and PGI, formation following thyroid hormone treatment (1 l), calcium release elicited by T4 and T, in the present investigation was not inhibited by indomethacin, and T, treatment did not increase PGE, and PGI, formation. In a recent study by Klaushofer et al (1 1) using neonatal mouse calvariae, it was reported that the percentage of calcium released following thyroid hormone administration showed greater variation than did release stimulated by other resorptive agents.…”

Section: T4 and T Stimulation Of Bone Resorptioncontrasting

confidence: 99%

“…inhibitory influence of calcitonin. This lack of "escape" by the thyroid hormones has been observed previously by other investigators using neonatal mouse calvariae for study (9,11). However, the reason for this sustained effect of calci-tonin is unclear.…”

Section: Discussionsupporting

confidence: 61%

“…thought to be independent of prostaglandin production (7,8), it has been suggested that the resorptive action of the thyroid hormones in neonatal mouse calvariae is prostaglandin-dependent (8, 9). Prostaglandins are believed to be important local regulators of bone resorption (1 3).…”

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confidence: 99%

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Prostaglandin-Independent Stimulation of Bone Resorption in Mouse Calvariae and in Isolated Rat Osteoclasts by Thyroid Hormones (T4, and T3)

Conaway

Ransjö

Lerner

1998

Experimental Biology and Medicine

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The thyroid hormones, thyroxine (T4) and triiodothyronine (T3), were found to enhance both neonatal mouse calvarial bone resorption and pit formation on bovine slices by isolated rat osteoclasts. Dosage-dependent release of 45Ca from mouse calvarial bones was observed after 120 hr of culture with 10(-6)-10(-8) MT4 and 10(-6)-10(-10) M T3. Maximum treatment/control ratios of 45Ca release were recorded for 10(-7) M T4 and 10(-8) MT3. Inhibition of 45Ca release stimulated by 10(-8) M T3 was observed in the presence of 30 nM salmon calcitonin at 48 hr and 120 hr of culture with no indication of "escape" by T3-treated bones. In contrast, stimulation of 45Ca release from mouse calvarial bones by 10(-7) MT4 and 10(-8) MT3 was not inhibited by 10(-6) M indomethacin. Formation of PGE2 and PGI2 (evaluated by measuring 6-keto-PGF1alpha) by mouse calvariae was also not increased by 10(-8) MT3 after 120 hr of culture. Furthermore, no increases in cAMP formation were observed in calvarial bone cultures after either 10 min or 24 hr of exposure to 10(-8) MT3. However, significant inhibition of 45Ca release stimulated by 10(-8) M T3 was found at 120 hr in the presence of 10(-3) M hydroxyurea. When isolated rat osteoclasts were cultured in the presence of 10(-7) MT3, a 1.4-fold stimulation of pit number was observed. Pit formation was not affected by addition of 10(-6) M indomethacin to either the control or T3-treated cultures. These data suggest that the stimulation of bone resorption in neonatal mouse calvariae and activation of isolated rat osteoclasts by the thyroid hormones is not related to either prostaglandin or cAMP formation. In mouse calvariae, the effect on bone resorption of the thyroid hormones is dependent on increased cellular replication, perhaps of osteoclast precursors, or other bone cells involved in the resorptive process.

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Section: Discussionsupporting

confidence: 91%

Section: T4 and T Stimulation Of Bone Resorptioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 61%

mentioning

confidence: 99%

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Prostaglandin-Independent Stimulation of Bone Resorption in Mouse Calvariae and in Isolated Rat Osteoclasts by Thyroid Hormones (T4, and T3)

Conaway

Ransjö

Lerner

1998

Experimental Biology and Medicine

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“…Medium ␤-glucuronidase activity was determined colorimetrically using phenolphthalein glucuronidate (Sigma, St. Louis, MO) as a substrate (31).…”

Section: ␤-Glucuronidase Activitymentioning

confidence: 99%

Cortisol Inhibits Acid-Induced Bone Resorption In Vitro

Krieger¹,

Frick²,

Bushinsky³

2002

Journal of the American Society of Nephrology

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Abstract. Metabolic acidosis increases urine calcium excretion without an increase in intestinal calcium absorption, resulting in a net loss of bone mineral. In vitro, metabolic acidosis has been shown to initially induce physicochemical mineral dissolution and then enhance cell-mediated bone resorption. Acidic medium stimulates osteoblastic prostaglandin E 2 production, which mediates the subsequent stimulation of osteoclastic bone resorption. Glucocorticoids are also known to decrease bone mineral density, and metabolic acidosis has been shown to increase glucocorticoid production. This study tested the hypothesis that glucocorticoids would exacerbate acid-induced net calcium efflux from bone. Neonatal mouse calvariae were cultured in acid (Acid; pH ϭ 7.06 Ϯ 0.01; [HCO 3 Ϫ ] ϭ 10.6 Ϯ 0.3 mM) or neutral (Ntl; pH ϭ 7.43 Ϯ 0.01; [HCO 3 Ϫ ] ϭ 26.2 Ϯ 0.5 mM) medium, with or without 1 M cortisol (Cort), and net calcium efflux and medium prostaglandin E 2 (PGE 2 ) levels and osteoclastic ␤-glucuronidase activity were determined. Compared with Ntl, Cort alone decreased calcium efflux, medium PGE 2 , and osteoclast activity; Acid led to an increase in all three parameters. The addition of Cort to Acid led to a reduction of calcium efflux, medium PGE 2 levels and ␤-glucuronidase activity compared with Acid alone. There was a significant direct correlation between medium PGE 2 concentration and net calcium efflux (r ϭ 0.944; n ϭ 23; P Ͻ 0.0001), between osteoclastic ␤-glucuronidase activity and net calcium efflux (r ϭ 0.663; n ϭ 40; P Ͻ 0.001), and between medium PGE 2 concentration and ␤Ϫglucuronidase activity (r ϭ 0.976; n ϭ 4; P Ͻ 0.01). Thus, in vitro cortisol inhibits acid-induced, cell-mediated osteoclastic bone resorption through a decrease in osteoblastic PGE 2 production. These results suggest that the osteopenia observed in response to metabolic acidosis in vivo is not due to an increase in endogenous cortisol production.

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Characterization of specific thyroid hormone receptors in bone

Krieger

Stappenbeck

Stern

1988

Journal of Bone and Mineral Research

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Thyroid hormones stimulate bone turnover in vivo and increase Ca release from bone in vitro. To investigate further the effects of thyroid hormones in bone, we have characterized specific nuclear receptors for [125I]tri-iodothyronine (T3) in neonatal mouse calvaria. Maximal specific binding of [125I]T3 to isolated nuclei occurred within 60 min at 22 degrees C. [125I]T3 binding was completely and rapidly displaced by the addition of 10(-6) M unlabeled T3; the dissociation appears to be first order with t1/2 = 36 min. The IC50 for competition by unlabeled T3 was approximately 10(-8) M. The relative affinity of thyroxine (T4) for the receptor was approximately 10 X lower than T3, consistent with its lower biological potency in most target tissues for thyroid hormones. Only weak competition was observed with diiodotyrosine at concentrations up to 10(-4) M. We have previously shown that the cardiotonic agent milrinone stimulates bone resorption in vitro with characteristics similar to those of T4. Structural homology between milrinone and T4 was recently reported. Milrinone, like diiodotyrosine, was only a weak competitor for binding at concentrations up to 10(-4) M. Milrinone inhibited collagen synthesis in the calvaria. The results suggest that the effects of milrinone on bone turnover in calvaria in vitro are probably not mediated through a thyroid hormone receptor.

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Cardiotonic agent milrinone stimulates resorption in rodent bone organ culture.

Cited by 19 publications

References 19 publications

Prostaglandin-Independent Stimulation of Bone Resorption in Mouse Calvariae and in Isolated Rat Osteoclasts by Thyroid Hormones (T4, and T3)

Prostaglandin-Independent Stimulation of Bone Resorption in Mouse Calvariae and in Isolated Rat Osteoclasts by Thyroid Hormones (T4, and T3)

Cortisol Inhibits Acid-Induced Bone Resorption In Vitro

Characterization of specific thyroid hormone receptors in bone

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