Robert Brommage - Academia.edu (original) (raw)

Papers by Robert Brommage

The New England journal of medicine, Jan 30, 2016

Cortical-bone fragility is a common feature in osteoporosis that is linked to nonvertebral fractu... more Cortical-bone fragility is a common feature in osteoporosis that is linked to nonvertebral fractures. Regulation of cortical-bone homeostasis has proved elusive. The study of genetic disorders of the skeleton can yield insights that fuel experimental therapeutic approaches to the treatment of rare disorders and common skeletal ailments. We evaluated four patients with Pyle's disease, a genetic disorder that is characterized by cortical-bone thinning, limb deformity, and fractures; two patients were examined by means of exome sequencing, and two were examined by means of Sanger sequencing. After a candidate gene was identified, we generated a knockout mouse model that manifested the phenotype and studied the mechanisms responsible for altered bone architecture. In all affected patients, we found biallelic truncating mutations in SFRP4, the gene encoding secreted frizzled-related protein 4, a soluble Wnt inhibitor. Mice deficient in Sfrp4, like persons with Pyle's disease, hav...

American Journal of Obstetrics and Gynecology, 2008

American Journal of Physiology Renal Physiology, Apr 1, 1984

The role of 1,25-dihydroxyvitamin D3 in regulating the maternal-to-fetal transfer of calcium and ... more The role of 1,25-dihydroxyvitamin D3 in regulating the maternal-to-fetal transfer of calcium and phosphorus across the placenta was examined by measuring maternal and fetal plasma levels of these elements in vitamin D-replete and -deficient rats. Pregnant rats in their 20th day of gestation and their fetuses were studied. Two diets with different calcium and phosphorus contents were used to produce either hypocalcemia or hypophosphatemia in the vitamin D-deficient rats. Calcium and phosphorus levels in fetal plasma were always higher than maternal values, and in vitamin D deficiency a twofold gradient of calcium and a fivefold gradient of phosphorus concentrations across the placenta were observed. Since protein levels in fetal plasma were approximately fivefold lower than maternal values, protein binding does not account for the higher fetal than maternal concentrations of plasma calcium. These results, together with previous data showing normal calcium content of vitamin D-deficient fetuses, indicate that 1,25-dihydroxyvitamin D3 and other vitamin D3 metabolites are not involved in the active transport of calcium and phosphorus across the placenta in the rat.

Endocrine Reviews, Jul 1, 2013

Endocrinology, Dec 18, 2014

In this study, we evaluated the role of WNT16 in regulating bone size, an important determinant o... more In this study, we evaluated the role of WNT16 in regulating bone size, an important determinant of bone strength. Mice with targeted disruption of the Wnt16 gene exhibited a 24% reduction in tibia cross-sectional area at 12 weeks of age compared with that of littermate wild-type (WT) mice. Histomorphometric studies revealed that the periosteal bone formation rate and mineral apposition rate were reduced (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .05) by 55% and 32%, respectively, in Wnt16 knockout (KO) vs WT mice at 12 weeks of age. In contrast, the periosteal tartrate resistant acid phosphatase-labeled surface was increased by 20% in the KO mice. Because mechanical strain is an important physiological regulator of periosteal bone formation (BF), we determined whether mechanical loading-induced periosteal BF is compromised in Wnt16 KO mice. Application of 4800-μe strain to the right tibia using a 4-point bending loading method for 2 weeks (2-Hz frequency, 36 cycles per day, 6 days/wk) produced a significant increase in cross-sectional area (11% above that of the unloaded left tibia, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .05, n = 6) in the WT but not in the KO mice (-0.2% change). Histomorphometric analyses revealed increases in the periosteal bone formation rate and mineral apposition rate in the loaded bones of WT but not KO mice. Wnt16 KO mice showed significant (20%-70%) reductions in the expression levels of markers of canonical (β-catenin and Axin2) but not noncanonical (Nfatc1 and Tnnt2) WNT signaling in the periosteum at 5 weeks of age. Our findings suggest that WNT16 acting via canonical WNT signaling regulates mechanical strain-induced periosteal BF and bone size.

American Journal of Physiology Endocrinology and Metabolism, Mar 1, 1984

Vitamin D deficiency was induced in lactating rats and their pups by placing female rats on a vit... more Vitamin D deficiency was induced in lactating rats and their pups by placing female rats on a vitamin D-deficient diet immediately after mating. Evidence of vitamin D deficiency included undetectable plasma levels of 25-hydroxyvitamin D3 in the dams, maternal hypocalcemia, the lack of pup growth, and pup hypocalcemia following starvation. This method of producing vitamin D-deficient pups was then used to determine whether the failure of vitamin D-deficient pups to grow properly results from a maternal or neonatal defect. Vitamin D-deficient dams and pups were injected with either vitamin D3 or the ethanol vehicle, and pup growth was monitored over the subsequent 6 days. Providing vitamin D3 to the pups directly had no effect on their growth, but administering vitamin D3 to the dams resulted in a tripling of the pup growth rate. The failure of vitamin D3 to promote pup growth when given directly to the pups was not the result of their inability to metabolize the vitamin because these pups converted [3H]-vitamin D3 to 25(OH)D3, 24,25(OH)2D3, and 1,25(OH)2D3 as determined by comigration with standards on both straight and reverse phase high-performance liquid chromatography systems. These results demonstrate that a maternal defect is responsible for the growth failure observed in vitamin D-deficient rat pups.

Calcified Tissue Int, 2000

American Journal of Physiology Endocrinology and Metabolism, Feb 1, 1985

The effects of varying dietary calcium and phosphorus content, vitamin D deficiency, oophorectomy... more The effects of varying dietary calcium and phosphorus content, vitamin D deficiency, oophorectomy, adrenalectomy, and simultaneous pregnancy on bone mineral loss during lactation were examined in rats. Unless otherwise stated, the diet contained 0.47% calcium and 0.3% phosphorus and the rats were given 26 nmol of vitamin D3. Femur ash weights were determined after 21 days of lactation and on age-matched nonlactating rats. Decreasing dietary calcium to 0.02% caused an increased loss of bone mineral, whereas increasing dietary calcium to 1.4% increased plasma calcium levels to 12 mg/100 ml but did not diminish the bone mineral loss observed during lactation. Varying dietary phosphorus did not have a major effect on bone mineral loss during lactation. In vitamin D-deficient rats, bone mineral loss during lactation was independent of dietary calcium levels and slightly greater than the loss observed in vitamin D-replete rats fed the normal calcium diet. Oophorectomy and adrenalectomy did not produce changes in femur ash weights of nonlactating rats or reduce bone mineral loss during lactation. Rats mated during their postpartum estrus and thus simultaneously pregnant and lactating, lost the same amount of bone mineral as caused by lactation alone.

Bioorganic & medicinal chemistry letters, Jan 15, 2016

A group of small molecule thienopyrimidine inhibitors of Notum Pectinacetylesterase are described... more A group of small molecule thienopyrimidine inhibitors of Notum Pectinacetylesterase are described. We explored both 2-((5,6-thieno[2,3-d]pyrimidin-4-yl)thio)acetic acids and 2-((6,7-thieno[3,2-d]pyrimidin-4-yl)thio)acetic acids. In both series, highly potent, orally active Notum Pectinacetylesterase inhibitors were identified.

The Journal of Nutrition, Dec 1, 1993

Lactulose is a disaccharide analogue of lactose that is resistant to metabolism in the small inte... more Lactulose is a disaccharide analogue of lactose that is resistant to metabolism in the small intestine but not in the large intestine. The effects of lactulose and other sugars on intestinal Ca absorption were determined from the decrease in the 47Ca:47 Sc ratio between diet and feces after feeding male rats diets containing these sugars during a single night. Dietary lactulose was more potent than lactose in stimulating Ca absorption and was effective between 5 and 38 wk of age. The component sugars of lactulose, galactose and fructose, did not influence Ca absorption when provided together at concentrations equimolar to that of lactulose. The stimulation of Ca absorption by dietary lactulose increased as dietary Ca concentration was raised and was not influenced by prior injections of calcitriol. Lactulose must be present in the same meal as Ca to stimulate Ca absorption, but this stimulation was lost if the rats were fed lactulose continuously for 2 or 7 d prior to the test diet. Other sugars thought to be poorly absorbed in the small intestine (xylitol, lactobionate, arabinose, raffinose, pyroglutamate, sorbitol, gluconate and raftilose) stimulated Ca absorption to an identical extent as lactulose. Cecectomy did not influence the enhancement of Ca absorption by lactulose. These results indicate that sugars resistant to metabolism and absorption in the small intestine but not the large intestine stimulate Ca absorption in the small intestine.

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Bioorganic & Medicinal Chemistry Letters, 2016

A group of small molecule thienochromenes inhibitors of Notum Pectinacetylesterase are described.... more A group of small molecule thienochromenes inhibitors of Notum Pectinacetylesterase are described. We developed SAR on three series based on carbon, oxygen and sulfur replacement of the 5-position. In each series, highly potent Notum Pectinacetylesterase inhibitors were identified.

Bone, 1995

The action of systematically administered recombinant human insulinlike growth factor-I (rhlGF-I)... more The action of systematically administered recombinant human insulinlike growth factor-I (rhlGF-I) complexed to its natural binding protein-3 (rhlGFBP-3) on cortical bone dynamic, structural, and mechanical properties was tested in previously ovariectomized (Ovx) rats. Bilateral ovariectomy or sham surgery was performed on 16-week-old female Sprague-Dawley rats. Eight weeks after surgery basal Sham and Ovx rats were killed to establish baseline cortical bone values before the initiation of treatment with rhlGF-I/IGFBP-3 complex. At that time, Ovx rats had increased body weight and body fat mass with reduced femoral BMC and BMD relative to basal Shams. Bone formation rates in Ovx rats were increased on both cortical envelopes relative to timematched controls. The thickness of the inner iamellar bone layer and average cortical width were reduced due to increased endocortical erosion. A similar ratio between Sham and Ovx rats in body mass and composition and femoral BMC and BMD continued throughout the experiment. Sixteen weeks after surgery bone formation rates at both cortical envelopes in Ovx rats were reduced relative to Shams, but endocortical erosion remained high causing a further decrease in thickness of the inner lamellar layer. As a result of periosteal bone modeling, Ovx rats exhibited a larger femoral cross-sectional area and periosteal perimeter, as well as a thicker outer lamellar layer. Newly deposited periosteal bone increased ultimate torque values in the Ovx rats relative to Shams at 16 weeks. Treatment of Ovx rats with the rhIGF-I/IGFBP-3 complex increased body weight, lean body mass, and femoral BMC and BMD. Bone formation was increased at both cortical envelopes resulting in a deposition of normal lamellar bone layers. Endocortical erosion remained similar to values seen in Sham rats. Envelope-specific changes following rhIGF-I/IGFBP-3 treatment resulted in a thicker cortex, higher polar moment of inertia and torque to failure relative to Ovx and Sham values, suggesting that this formulation may be of benefit in the treatment of various ostopenias.

American Journal of Physiology Endocrinology and Metabolism, Apr 1, 1984

Pups raised by lactating rats deficient in vitamin D do not grow normally, and we have shown prev... more Pups raised by lactating rats deficient in vitamin D do not grow normally, and we have shown previously that this growth failure results from a maternal rather than a neonatal defect. This result indicates that vitamin D-deficient rats produce reduced amounts of milk and/or the milk they do produce is nutritionally incomplete. To examine the first of these possibilities, 3H2O and 42K in separate experiments were given to lactating rats at 13 days postpartum, and the amount of isotope transferred to their pups during the next 24 h was determined. The amount of milk produced during this period was calculated from the measured concentrations of 3H2O and 42K in milk. The specific activity of 3H2O in maternal plasma was kept constant by providing 3H2O in the drinking water of the dams. Vitamin D-deficient rats were found to produce only 19.5 +/- 1.8% determined by the 3H2O method and 23.2 +/- 1.1% by the 42K method (means +/- SD) of the amount of milk produced by vitamin D-replete rats. The composition of milk from vitamin D-deficient rats was examined to determine its nutritional value. Vitamin D-deficient milk contains elevated levels of fat, and the skim fraction contains more protein, potassium, calcium, and inorganic phosphorus but less carbohydrate than normal milk. When vitamin D-deficient dams were given two pups to nurse rather than the eight usually provided, pup growth was equivalent to that of vitamin D-replete pups. Furthermore, femur dry weights and degree of mineralization were similar in vitamin D-deficient and -replete pups of equivalent body weight.(ABSTRACT TRUNCATED AT 250 WORDS)

The Journal of Nutrition, Aug 1, 1984

Lactating and nonlactating rats, both deficient and replete in cholecalciferol, were allowed a fr... more Lactating and nonlactating rats, both deficient and replete in cholecalciferol, were allowed a free selection among three diets containing 0.47 % Ca, 0.3 % P (normal Ca, normal P diet); 2.0% Ca, 0.3% P (high Ca diet); and 0.47% Ca, 1.0% P (high P diet). An additional group of vitamin D-deficient lactating rats was fed only the normal Ca, normal P diet. Vitamin D-deficient rats showed a strong selection preference for the high Ca diet but avoided the high P diet, whereas cholecalciferolreplete rats consumed the normal Ca, normal P diet predominantly.

Experientia, Jun 1, 1986

Chick embryos from vitamin D-deficient hens given physiological doses of 1,25-dihydroxyvitamin D3... more Chick embryos from vitamin D-deficient hens given physiological doses of 1,25-dihydroxyvitamin D3 or 24,25-dihydroxyvitamin D 3 or both become severely hypocaleemic; hyperphosphatemic and fail to hatch as compared to those derived from hens given 25-hydroxyvitamin D 3 or 24,25-difluoro-25-hydroxyvitamin D 3. Calvariae from the former contain less mineral and on incubation in vitro produce significantly lower calcium and higher phosphate concentration in the medium than do the ealvariae derived from the embryos of hens supported on 25-hydroxyvitamin D 3 or 24,24-difluoro-25-hydroxyvitamin D 3.

BoneKEy reports, 2015

Disruption of serotonin synthesis in neurons and the periphery by knockout (KO) of mouse genes fo... more Disruption of serotonin synthesis in neurons and the periphery by knockout (KO) of mouse genes for tryptophan hydroxylases (peripheral Tph1 and neuronal Tph2) has been claimed to decrease (Tph2 KO) and increase (Tph1 KO) bone mass. In this report, adult male and female Tph2 KO mice were observed to have elevated spine trabecular bone. Female Tph2 KO mice have reduced midshaft femur cortical bone thickness. Bone mass was normal in male and female Tph1 KO mice examined as part of a Tph1/Tph2 double knockout (DKO) mouse cohort.

Frontiers in endocrinology, 2015

After creating >4,650 knockouts (KOs) of independent mouse genes, we screened them by high-thr... more After creating >4,650 knockouts (KOs) of independent mouse genes, we screened them by high-throughput phenotyping and found that cannabinoid receptor 1 (Cnr1) KO mice had the same lean phenotype published by others. We asked if our KOs of DAG lipase α or β (Dagla or Daglb), which catalyze biosynthesis of the endocannabinoid (EC) 2-arachidonoylglycerol (2-AG), or Napepld, which catalyzes biosynthesis of the EC anandamide, shared the lean phenotype of Cnr1 KO mice. We found that Dagla KO mice, but not Daglb or Napepld KO mice, were among the leanest of 3651 chow-fed KO lines screened. In confirmatory studies, chow- or high fat diet-fed Dagla and Cnr1 KO mice were leaner than wild-type (WT) littermates; when data from multiple cohorts of adult mice were combined, body fat was 47 and 45% lower in Dagla and Cnr1 KO mice, respectively, relative to WT values. By contrast, neither Daglb nor Napepld KO mice were lean. Weanling Dagla KO mice ate less than WT mice and had body weight (BW) s...

The American journal of physiology, 1984