Low Bone Turnover and Low BMD in Down Syndrome: Effect of Intermittent PTH Treatment

Fowler, Tristan W.; McKelvey, Kent D.; Akel, Nisreen; Schilden, Jaclyn Vander; Bacon, A. W.; Bracey, John W.; Sowder, Timothy; Skinner, Robert A.; Swain, Frances L.; Hogue, William R.; Leblanc, Donna B.; Gaddy, Dana; Wenger, Galen R.; Suva, Larry J.

doi:10.1371/journal.pone.0042967

Cited by 44 publications

(61 citation statements)

References 47 publications

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“…The skeletal phenotype of the homozygous Sc65Mut mice was characterized in detail as we have described . Skeletal preparations of newborn pups did not show any macroscopic differences or patterning defects between Sc65Mut and WT genotypes (data not shown).…”

Section: Resultsmentioning

confidence: 91%

Sc65 Is a Novel Endoplasmic Reticulum Protein That Regulates Bone Mass Homeostasis

Gruenwald

Castagnola

Besio

et al. 2013

Journal of Bone and Mineral Research

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Members of the Leprecan family of proteins include enzymes, prolyl 3-hydroxylase 1 (P3h1), P3h2 and P3h3, and non-enzymatic proteins, Crtap and Sc65. Mutations in CRTAP and LEPRE1 (encoding P3H1) have been associated with human disease such as recessive osteogenesis imperfecta, however, the function of Sc65 which is closely related and highly homologous to Crtap is unknown. Sc65 has been described as a synaptonemal complex protein, a nucleolar protein, and a cytoplasmic adapter protein. In light of its high sequence similarity with Crtap, an endoplasmic reticulum (ER)-associated protein, and the importance of post-translational modifications such as collagen prolyl 3-hydroxylation in bone metabolism, we hypothesized that Sc65 was an ER-resident protein that would have an important role in bone homeostasis. In this study, we demonstrate that Sc65 is a previously unrecognized ER protein, and that it does not localize in the nucleus of somatic cells. Moreover, Sc65 is expressed and functional during skeletal development since loss of Sc65 results in a progressive osteopenia that affects both trabecular and cortical bone. Bone loss is due to increased bone resorption mediated by a non-cell autonomous effect on osteoclasts. Therefore, Sc65, like its related family member Crtap, is an important modulator of bone homeostasis, acting as a negative regulator of osteoclastogenesis.

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Section: Resultsmentioning

confidence: 91%

Sc65 Is a Novel Endoplasmic Reticulum Protein That Regulates Bone Mass Homeostasis

Gruenwald

Castagnola

Besio

et al. 2013

Journal of Bone and Mineral Research

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“…Formalin-fixed tibiae and femora from tumor bearing mice and controls, as well as from IL-8 transgenic mice were imaged using a MicroCT 40 (Scanco Medical AG, Bassersdorf, Switzerland) using a 12 µm isotropic voxel size in all dimensions as described previously [27]. Three-dimensional reconstructions were created by stacking the regions of interest from each two-dimensional slice and then applying a gray-scale threshold and Gaussian noise filter as described [27] using a consistent and predetermined threshold (245) with all data acquired at 55 kVp, 114 mA, and 200-ms integration time. Fractional bone volume (bone volume/tissue volume; BV/TV) and architectural properties of trabecular bone (trabecular thickness (Tb.Th.…”

Section: Methodsmentioning

confidence: 99%

“…This calculation was performed on all 25 slices (1 slice = ~12.5 µm), using the average for the final calculation. The outer and inner perimeter of the cortical midshaft was determined by a three-dimensional triangulation of the bone surface (BS) of the 25 slices, and cortical thickness and other cortical parameters were determined as described [27, 28]. For bone phenotype assessment of IL-8 transgenic mice, 10 male and 6 female IL-8 transgenic mice (4 months) and 9 male and 6 female WT littermate controls were examined.…”

Section: Methodsmentioning

confidence: 99%

Circulating interleukin-8 levels explain breast cancer osteolysis in mice and humans

Kamalakar

Bendre

Washam

et al. 2014

Bone

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Skeletal metastases of breast cancer and subsequent osteolysis connote a dramatic change in the prognosis for the patient and significantly increase the morbidity associated with disease. The cytokine Interleukin 8 (IL-8/CXCL8) is able to directly stimulate osteoclastogenesis and bone resorption in mouse models of breast cancer bone metastasis. In this study, we determined whether circulating levels of IL-8 were associated with increased bone resorption and breast cancer bone metastasis in patients, and investigated IL-8 action in vitro and in vivo in mice. Using breast cancer patient plasma (36 patients), we identified significantly elevated IL-8 levels in bone metastasis patients compared with patients lacking bone metastasis (p<0.05), as well as a correlation between plasma IL-8 and increased bone resorption (p<0.05), as measured by NTx levels. In a total of 22 ER+ and 15 ER− primary invasive ductal carcinomas, all cases examined stained positive for IL-8 expression. In vitro, human MDA-MB-231 and MDA-MET breast cancer cell lines secrete two distinct IL-8 isoforms, both of which were found to stimulate osteoclastogenesis. However, the more osteolytic MDA-MET–derived full length IL-8(1–77) had significantly higher potency than the non-osteolytic MDA-MB-231-derived IL-8(6–77), via the CXCR1 receptor. MDA-MET breast cancer cells were injected into the tibia of nude mice and 7 days later treated daily with a neutralizing IL-8 monoclonal antibody. All tumor-injected mice receiving no antibody developed large osteolytic bone tumors, whereas 83% of the IL-8 antibody-treated mice had no evidence of tumor at the end of 28 days and had significantly increased survival. The pro-osteoclastogenic activity of IL-8 in vivo was confirmed when transgenic mice expressing human IL-8 were examined and found to have a profound osteopenic phenotype, with elevated bone resorption and inherently low bone mass. Collectively, these data suggest that IL-8 plays an important role in breast cancer osteolysis and that anti-IL-8 therapy may be useful in the treatment of the skeletal related events associated with breast cancer.

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“…For skeletal parameters in DS mouse models, we and others have identified significant deficits in BMD, trabecular bone parameters (thickness, separation and number) and cortical bone measures in Ts65Dn mice compared to euploid control mice [17]. Significant deficits in mineral apposition rate (MAR), bone formation rate (BFR), and strength properties in trisomic mice compared to controls were also observed [17, 26, 27]. …”

Section: Introductionmentioning

confidence: 97%

Epigallocatechin-3-gallate (EGCG) consumption in the Ts65Dn model of Down syndrome fails to improve behavioral deficits and is detrimental to skeletal phenotypes

Stringer

Abeysekera

Thomas

et al. 2017

Physiology & Behavior

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Down syndrome (DS) is caused by three copies of human chromosome 21 (Hsa21) and results in phenotypes including intellectual disability and skeletal deficits. Ts65Dn mice have three copies of ~50% of the genes homologous to Hsa21 and display phenotypes associated with DS, including cognitive deficits and skeletal abnormalities. DYRK1A is found in three copies in humans with Trisomy 21 and in Ts65Dn mice, and is involved in a number of critical pathways including neurological development and osteoclastogenesis. Epigallocatechin-3-gallate (EGCG), the main polyphenol in green tea, inhibits Dyrk1a activity. We have previously shown that EGCG treatment (~10mg/kg/day) improves skeletal abnormalities in Ts65Dn mice, yet the same dose, as well as ~20mg/kg/day did not rescue deficits in the Morris water maze spatial learning task (MWM), novel object recognition (NOR) or balance beam task (BB). In contrast, a recent study reported that an EGCG-containing supplement with a dose of 2–3 mg per day (~40–60mg/kg/day) improved hippocampal-dependent task deficits in Ts65Dn mice. The current study investigated if an EGCG dosage similar to that study would yield similar improvements in either cognitive or skeletal deficits. Ts65Dn mice and euploid littermates were given EGCG [0.4 mg/mL] or a water control, with treatments yielding average daily intakes of ~50 mg/kg/day EGCG, and tested on the multivariate concentric square field (MCSF)—which assesses activity, exploratory behavior, risk assessment, risk taking, and shelter seeking—and NOR, BB, and MWM. EGCG treatment failed to improve cognitive deficits; EGCG also produced several detrimental effects on skeleton in both genotypes. In a refined HPLC-based assay, its first application in Ts65Dn mice, EGCG treatment significantly reduced kinase activity in femora but not in the cerebral cortex, cerebellum, or hippocampus. Counter to expectation, 9-week-old Ts65Dn mice exhibited a decrease in Dyrk1a protein levels in Western blot analysis in the cerebellum. The lack of beneficial therapeutic behavioral effects and potentially detrimental skeletal effects of EGCG found in Ts65Dn mice emphasize the importance of identifying dosages of EGCG that reliably improve DS phenotypes and linking those effects to actions of EGCG (or EGCG-containing supplements) in specific targets in brain and bone.

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Low Bone Turnover and Low BMD in Down Syndrome: Effect of Intermittent PTH Treatment

Cited by 44 publications

References 47 publications

Sc65 Is a Novel Endoplasmic Reticulum Protein That Regulates Bone Mass Homeostasis

Sc65 Is a Novel Endoplasmic Reticulum Protein That Regulates Bone Mass Homeostasis

Circulating interleukin-8 levels explain breast cancer osteolysis in mice and humans

Epigallocatechin-3-gallate (EGCG) consumption in the Ts65Dn model of Down syndrome fails to improve behavioral deficits and is detrimental to skeletal phenotypes

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