Publications by authors named "J C Fritton"

26 Publications

Bone Growth is Influenced by Fructose in Adolescent Male Mice Lacking Ketohexokinase (KHK).

Calcif Tissue Int 2020 05 29;106(5):541-552. Epub 2020 Jan 29.

Department of Biomedical Engineering, Graduate School, Rutgers University, New Brunswick, NJ, USA.

Fructose is metabolized in the cytoplasm by the enzyme ketohexokinase (KHK), and excessive consumption may affect bone health. Previous work in calcium-restricted, growing mice demonstrated that fructose disrupted intestinal calcium transport. Thus, we hypothesized that the observed effects on bone were dependent on fructose metabolism and took advantage of a KHK knockout (KO) model to assess direct effects of high plasma fructose on the long bones of growing mice. Four groups (n = 12) of 4-week-old, male, C57Bl/6 background, congenic mice with intact KHK (wild-type, WT) or global knockout of both isoforms of KHK-A/C (KHK-KO), were fed 20% glucose (control diet) or fructose for 8 weeks. Dietary fructose increased by 40-fold plasma fructose in KHK-KO compared to the other three groups (p < 0.05). Obesity (no differences in epididymal fat or body weight) or altered insulin was not observed in either genotype. The femurs of KHK-KO mice with the highest levels of plasma fructose were shorter (2%). Surprisingly, despite the long-term blockade of KHK, fructose feeding resulted in greater bone mineral density, percent volume, and number of trabeculae as measured by µCT in the distal femur of KHK-KO. Moreover, higher plasma fructose concentrations correlated with greater trabecular bone volume, greater work-to-fracture in three-point bending of the femur mid-shaft, and greater plasma sclerostin. Since the metabolism of fructose is severely inhibited in the KHK-KO condition, our data suggest mechanism(s) that alter bone growth may be related to the plasma concentration of fructose.
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http://dx.doi.org/10.1007/s00223-020-00663-wDOI Listing
May 2020

Dose-Dependent Growth Delay of Breast Cancer Xenografts in the Bone Marrow of Mice Treated with Ra: The Role of Bystander Effects and Their Potential for Therapy.

J Nucl Med 2020 01 13;61(1):89-95. Epub 2019 Sep 13.

Department of Radiology, New Jersey Medical School, Rutgers University, Newark, New Jersey

The role of radiation-induced bystander effects in radiation therapy remains unclear. With renewed interest in therapy with α-particle emitters, and their potential for sterilizing disseminated tumor cells (DTCs), it is critical to determine the contribution of bystander effects to the overall response so they can be leveraged for maximum clinical benefit. Female athymic nude mice were administered 0, 50, or 600 kBq/kg RaCl to create bystander conditions. At 24 hours after administration, MDA-MB-231 or MCF-7 human breast cancer cells expressing luciferase were injected into the tibial marrow compartment. Tumor burden was tracked weekly via bioluminescence. The MDA-MB-231 xenografts were observed to have a 10-day growth delay in the 600 kBq/kg treatment group only. In contrast, MCF-7 cells had 7- and 65-day growth delays in the 50 and 600 kBq/kg groups, respectively. Histologic imaging of the tibial marrow compartment, α-camera imaging, and Monte Carlo dosimetry modeling revealed DTCs both within and beyond the range of the α-particles emitted from Ra in bone for both MCF-7 and MDA-MB-231 cells. Taken together, these results support the participation of Ra-induced antiproliferative/cytotoxic bystander effects in delayed growth of DTC xenografts. They indicate that the delay depends on the injected activity and therefore is dose-dependent. They suggest using RaCl as an adjuvant treatment for select patients at early stages of breast cancer.
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http://dx.doi.org/10.2967/jnumed.119.227835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954456PMC
January 2020

Fructose malabsorption induces cholecystokinin expression in the ileum and cecum by changing microbiota composition and metabolism.

FASEB J 2019 06 2;33(6):7126-7142. Epub 2019 Apr 2.

Micalis Institute, Institut National de la Recherche Agronomique (INRA), AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France.

Current fructose consumption levels often overwhelm the intestinal capacity to absorb fructose. We investigated the impact of fructose malabsorption on intestinal endocrine function and addressed the role of the microbiota in this process. To answer this question, a mouse model of moderate fructose malabsorption [ketohexokinase mutant (KHK)] and wild-type (WT) littermate mice were used and received a 20%-fructose (KHK-F and WT-F) or 20%-glucose diet. Cholecystokinin () mRNA and protein expression in the ileum and cecum, as well as preproglucagon () and neurotensin () mRNA expression in the cecum, increased in KHK-F mice. In KHK-F mice, triple-label immunohistochemistry showed major up-regulation of CCK in enteroendocrine cells (EECs) that were glucagon-like peptide-1 (GLP-1)/Peptide YY (PYY) in the ileum and colon and GLP-1/PYY in the cecum. The cecal microbiota composition was drastically modified in the KHK-F in association with an increase in glucose, propionate, succinate, and lactate concentrations. Antibiotic treatment abolished fructose malabsorption-dependent induction of cecal mRNA expression and, in mouse GLUTag and human NCI-H716 cells, mRNA expression levels increased in response to propionate, both suggesting a microbiota-dependent process. Fructose reaching the lower intestine can modify the composition and metabolism of the microbiota, thereby stimulating the production of CCK from the EECs possibly in response to propionate.-Zhang, X., Grosfeld, A., Williams, E., Vasiliauskas, D., Barretto, S., Smith, L., Mariadassou, M., Philippe, C., Devime, F., Melchior, C., Gourcerol, G., Dourmap, N., Lapaque, N., Larraufie, P., Blottière, H. M., Herberden, C., Gerard, P., Rehfeld, J. F., Ferraris, R. P., Fritton, J. C., Ellero-Simatos, S., Douard, V. Fructose malabsorption induces cholecystokinin expression in the ileum and cecum by changing microbiota composition and metabolism.
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http://dx.doi.org/10.1096/fj.201801526RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988857PMC
June 2019

The effects of estrogen deficiency on cortical bone microporosity and mineralization.

Bone 2018 05 31;110:1-10. Epub 2018 Jan 31.

Department of Biomedical Engineering, The City College of New York, New York, NY 10031, United States. Electronic address:

Recent studies have demonstrated matrix-mineral alterations in bone tissue surrounding osteocytes in estrogen-deficient animals. While cortical bone porosity has been shown to be a contributor to the mechanical properties of bone tissue, little analysis has been done to investigate the effects of estrogen deficiency on bone's microporosities, including the vascular and osteocyte lacunar porosities. In this study we examined alterations in cortical bone microporosity, mineralization, and cancellous bone architecture due to estrogen deficiency in the ovariectomized rat model of postmenopausal osteoporosis. Twenty-week-old female Sprague-Dawley rats were subjected to either ovariectomy or sham surgery. Six weeks post-surgery tibiae were analyzed using high-resolution micro-CT, backscattered electron imaging, nanoindentation, and dynamic histomorphometry. Estrogen deficiency caused an increase in cortical bone vascular porosity, with enlarged vascular pores and little change in tissue mineral density in the proximal tibial metaphysis. Measurements of cancellous architecture corresponded to previous studies reporting a decrease in bone volume fraction, an increase in trabecular separation, and a decrease in trabecular number in the proximal tibia due to estrogen deficiency. Nanoindentation results showed no differences in matrix stiffness in osteocyte-rich areas of the proximal tibia of estrogen-deficient rats, and bone labeling and backscattered electron imaging showed no significant changes in mineralization around the vascular pores. The findings demonstrate local surface alterations of vascular pores due to estrogen deficiency. An increase in cortical vascular porosity may diminish bone strength as well as alter bone mechanotransduction via interstitial fluid flow, both of which could contribute to bone fragility during postmenopausal osteoporosis.
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http://dx.doi.org/10.1016/j.bone.2018.01.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377161PMC
May 2018

Effects of the basic multicellular unit and lamellar thickness on osteonal fatigue life.

J Biomech 2017 07 23;60:116-123. Epub 2017 Jun 23.

Department of Orthopaedics & Graduate School of Biomedical Sciences, New Jersey Medical School, Rutgers University, 205 South Orange Avenue, Newark, NJ 07103, USA; Department of Biomedical Engineering, School of Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ 08854, USA. Electronic address:

A remodeling cycle sets the size of the osteon and associated lamellae in the basic multicellular unit. Treatments and aging affect these micro-structural features. We previously demonstrated decreased fatigue life with an unexplained mechanism and decreased osteon size in cortical bone treated with high-dose bisphosphonate. Here, three finite element models were examined: type-1: a single osteon, as a homogeneous unit and with heterogeneous lamellae and interlamellae, type-2: a control, interstitial-only tissue and type-3: the osteon with cement line, set within the interstitial tissue. Models were loaded in simulated, sinusoidal bending fatigue. As osteon size was decreased, lamellar number and lamellar thickness were incrementally adjusted for each model. As hypothesized, lamellae within the larger type-1 models attained greater cycles to failure and the addition of an osteon to type-2 models (generating a type-3 model set) yielded increased fatigue life. However, as the osteon size was decreased, the potential for compressive damage nucleation was increased within the lamellae of the osteons versus the interstitium. Also, osteons with fewer, thicker lamellae displayed increased fatigue life. Osteonal microstructure plays a role in damage initiation location, especially when BMU size is smaller. Previous findings by us and others could partially be explained by this further understanding of increased probability for damage nucleation in smaller osteons.
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http://dx.doi.org/10.1016/j.jbiomech.2017.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559899PMC
July 2017