scholarly journals A Role for the Calcitonin Receptor to Limit Bone Loss During Lactation in Female Mice by Inhibiting Osteocytic Osteolysis

Endocrinology ◽  
2015 ◽  
Vol 156 (9) ◽  
pp. 3203-3214 ◽  
Author(s):  
Michele V. Clarke ◽  
Patricia K. Russell ◽  
David M. Findlay ◽  
Stephen Sastra ◽  
Paul H. Anderson ◽  
...  
Keyword(s):  
Cortical Bone ◽  
Direct Action ◽  
Bone Matrix ◽  
Physiological Role ◽  
Mrna Levels ◽  
Calcitonin Receptor ◽  
Micro Computed Tomography ◽  
Littermate Control ◽  
Osteocytic Osteolysis ◽  
Osteocyte Lacunar

During lactation, the large transfer of calcium from the mother to the milk is primarily sourced from the maternal skeleton. To determine whether the calcitonin receptor (CTR) plays a physiological role to protect the skeleton from excessive resorption during lactation, we assessed the maternal skeleton of global CTR knockout (CTRKO) and littermate control mice at the end of lactation (postnatal day 21). Micro-computed tomography analyses showed no effect on trabecular or cortical bone in the distal femur and L1 vertebra of maternal global CTR deletion at the end of lactation in global CTRKO mice compared with that in control mice. Bone resorption, as assessed by osteoclast number and activity at the end of lactation, was unaffected by maternal CTR deletion. Cathepsin K, carbonic anhydrase 2, matrix metalloproteinase 13, and receptor activator of nuclear factor-κB ligand mRNA levels, however, were markedly elevated by 3- to 6.5-fold in whole bone of lactating global CTRKO females. Because these genes have been shown to be up-regulated in osteocytes during lactation when osteocytes resorb their surrounding bone matrix, together with their reported expression of the CTR, we determined the osteocyte lacunar area in cortical bone. After lactation, the top 20% of osteocyte lacunar area in global CTRKO mice was 10% larger than the top 20% in control mice. These data are consistent with an increased osteocytic osteolysis in global CTRKO mice during lactation, which is further supported by the increased serum calcium observed in global CTRKO mice after lactation. These results provide evidence for a physiological role for the CTR to protect the maternal skeleton during lactation by a direct action on osteocytes to inhibit osteolysis.

The calcitonin receptor regulates osteocyte lacunae acidity during lactation in mice

2021 ◽  
Vol 249 (1) ◽  
pp. 31-41
Author(s):  
Rachel A Davey ◽  
Michele V Clarke ◽  
Suzanne B Golub ◽  
Patricia K Russell ◽  
Jeffrey D Zajac
Keyword(s):  
Gene Expression ◽  
Direct Action ◽  
Physiological Role ◽  
Calcitonin Receptor ◽  
Ph Indicator ◽  
Osteocyte Lacunae ◽  
Osteocytic Osteolysis ◽  
Indicator Dye

The physiological role of calcitonin, and its receptor, the CTR (or Calcr), has long been debated. We previously provided the first evidence for a physiological role of the CTR to limit maternal bone loss during lactation in mice by a direct action on osteocytes to inhibit osteocytic osteolysis. We now extend these findings to show that CTR gene expression is upregulated two- to three-fold in whole bone of control mice at the end of pregnancy (E18) and lactation (P21) compared to virgin controls. This was associated with an increase in osteoclast activity evidenced by increases in osteoclast surface/bone surface and Dcstamp gene expression. To investigate the mechanism by which the CTR inhibits osteocytic osteolysis, in vivo acidification of the osteocyte lacunae during lactation (P14 days) was assessed using a pH indicator dye. A lower pH was observed in the osteocyte lacunae of lactating Global-CTRKOs compared to controls and was associated with an increase in the gene expression of ATPase H+ transporting V0 subunit D2 (Atp6v0d2) in whole bone of Global-CTRKOs at the end of lacation (P21). To determine whether the CTR is required for the replacement of mineral within the lacunae post-lactation, lacunar area was determined 3 weeks post-weaning. Comparison of the largest 20% of lacunae by area did not differ between Global-CTRKOs and controls post-lactation. These results provide evidence for CTR activation to inhibit osteocytic osteolysis during lactation being mediated by regulating the acidity of the lacunae microenvironment, whilst the CTR is dispensable for replacement of bone mineral within lacunae by osteocytes post-lactation.

PSX-A-3 Late-Breaking: Analysis of serum chemistry for metabolic function in GnRH-II receptor knockdown and littermate control boars

2021 ◽  
Vol 99 (Supplement_3) ◽  
pp. 377-377
Author(s):  
Caitlin E Ross ◽  
Amy T Desaulniers ◽  
Rebecca A Cederberg ◽  
Ginger A Mills ◽  
Clay A Lents ◽  
...  
Keyword(s):  
Equal Opportunity ◽  
Physiological Role ◽  
Lactic Dehydrogenase ◽  
High Density Lipoproteins ◽  
Mrna Levels ◽  
Gamma Glutamyl Transpeptidase ◽  
Littermate Control ◽  
Elevated Creatinine ◽  
Metabolic Disruption ◽  
And Control

Abstract Pigs are the only livestock species encoding functional proteins for both the second form of gonadotropin-releasing hormone (GnRH-II) and its receptor (GnRHR-II), which are uniquely expressed in reproductive and non-reproductive tissues. To examine the physiological role of the GnRH-II/GnRHR-II system, we produced a swine line with reduced endogenous levels of GnRHR-II (GnRHR-II KD); males exhibit 70% diminished testicular GnRHR-II mRNA levels and 82% reduced circulating testosterone concentrations. Given that testosterone impacts metabolism, blood was collected from GnRHR-II KD (n = 5) and littermate control (n = 5) boars via indwelling jugular catheters, with serum isolated and subjected to veterinary diagnostic panels for metabolic analyte examination (PhysLab, Lincoln, NE). Statistical analyses utilized the MIXED procedure of SAS; the model included line as fixed and litter as random effects. Creatine kinase and blood urea nitrogen (BUN):creatinine ratios were elevated, creatinine was reduced (P < 0.01), and thyroxine tended to be decreased (P < 0.10) in GnRHR-II KD compared with control boars. Glucose, BUN, amylase, and lipase levels were not different. Liver products differed in transgenic versus control boars; levels of lactic dehydrogenase, aspartate and alanine aminotransferases (AST; ALT), and gamma-glutamyl transpeptidase were higher, whereas AST:ALT ratios, total protein, albumin, and globulin levels were lower (P < 0.05) in GnRHR-II KD boars. Albumin:globulin ratios and bilirubin (total and direct) did not differ. Additionally, serum cholesterol was decreased (P < 0.05), non-high density lipoproteins (HDLs) and low density lipoproteins (LDLs) tended to be decreased (P < 0.10), and triglycerides, HDLs, and cholesterol:HDL ratios did not differ between GnRHR-II KD and control males. These data suggest metabolic disruption in GnRHR-II KD boars, which may be due to suppressed gonadal steroidogenesis or ubiquitous knockdown of GnRHR-II expression. Supported by USDA/NIFA AFRI (2017-67015-26508) and Hatch Multistate (NEB-26–244) funds. USDA is an equal opportunity provider and employer.

scholarly journals Reduced local mechanical stimuli in spaceflight diminishes osteocyte lacunar morphometry and spatial heterogeneity in mouse cortical bone

2022 ◽  
Author(s):  
Jennifer C. Coulombe ◽  
Zachary K. Mullen ◽  
Ashton M. Wiens ◽  
Liam E. Fisher ◽  
Maureen E. Lynch ◽  
...  
Keyword(s):  
Cortical Bone ◽  
Measurement Errors ◽  
Space Shuttle ◽  
Three Dimensional ◽  
Large Cell ◽  
Young Female ◽  
Mechanical Stimuli ◽  
Micro Computed Tomography ◽  
Osteocyte Lacunae ◽  
Osteocyte Lacunar

Three-dimensional (3D) imaging of osteocyte lacunae has recently substantiated the connection between lacunar shape and size, and osteocyte age, viability, and mechanotransduction. Yet it remains unclear why individual osteocytes reshape their lacunae and how networks of osteocytes change in response to local alterations in mechanical loads. We evaluated the effects of local mechanical stimuli on osteocyte lacunar morphometrics in tibial cortical bone from young female mice flown on the Space Shuttle for ~13 days. We optimized scan parameters, using a laboratory-based submicrometer-resolution X-Ray Microscope, to achieve large ~ 0.3 mm3 fields of view with sufficient resolution (≥ 0.3 μm) to visualize and measure thousands of lacunae per scan. Our novel approach avoids large measurement errors that are inherent in 2D and enables a facile 3D solution as compared to the lower resolution from benchtop micro-computed tomography (CT) systems or the cost and inaccessibility of synchrotron-based CT. Osteocyte lacunae were altered following microgravity exposure in a region-specific manner: more elongated (+7.0% Stretch) in predominately tensile-loaded bone as compared to those in compressively-loaded regions. In compressively-loaded bone, lacunae formed in microgravity were significantly larger (+6.9% Volume) than in the same region formed on Earth. We also evaluated lacunar heterogeneity (i.e., spatial autocorrelation of lacunar morphometric parameters) via kriging models. These statistical models demonstrated that heterogeneity varied with underlying spatial contributors, i.e. the local mechanical and biological environment. Yet in the absence of gravitational loading, osteocyte lacunae in newly formed bone were larger and were collectively more homogenous than in bone formed on Earth. Overall, this study shows that osteocyte reshape their lacunae in response to changes, or absence, in local mechanical stimuli and different biological environments. Additionally, spatial relationships among osteocytes are complex and necessitate evaluation in carefully selected regions of interest and of large cell populations.

scholarly journals The deletion of glucagon-like peptide-1 receptors expressing neurons in the dorsomedial hypothalamic nucleus disrupts the diurnal feeding pattern and induces hyperphagia and obesity

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Yuko Maejima ◽  
Shoko Yokota ◽  
Masaru Shimizu ◽  
Shoichiro Horita ◽  
Daisuke Kobayashi ◽  
...  
Keyword(s):  
Nucleus Tractus Solitarius ◽  
Physiological Role ◽  
Feeding Pattern ◽  
Hypothalamic Nucleus ◽  
Acid Decarboxylase ◽  
Mrna Levels ◽  
Dorsomedial Hypothalamic Nucleus ◽  
Fos Expression ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Abstract Background Feeding rhythm disruption contributes to the development of obesity. The receptors of glucagon-like peptide-1 (GLP-1) are distributed in the wide regions of the brain. Among these regions, GLP-1 receptors (GLP-1R) are expressed in the dorsomedial hypothalamic nucleus (DMH) which are known to be associated with thermogenesis and circadian rhythm development. However, the physiological roles of GLP-1R expressing neurons in the DMH remain elusive. Methods To examine the physiological role of GLP-1R expressing neurons in the DMH, saporin-conjugated exenatide4 was injected into rat brain DMH to delete GLP-1R-positive neurons. Subsequently, locomotor activity, diurnal feeding pattern, amount of food intake and body weight were measured. Results This deletion of GLP-1R-positive neurons in the DMH induced hyperphagia, the disruption of diurnal feeding pattern, and obesity. The deletion of GLP-1R expressing neurons also reduced glutamic acid decarboxylase 67 and cholecystokinin A receptor mRNA levels in the DMH. Also, it reduced the c-fos expression after refeeding in the suprachiasmatic nucleus (SCN). Thirty percent of DMH neurons projecting to the SCN expressed GLP-1R. Functionally, refeeding after fasting induced c-fos expression in the SCN projecting neurons in the DMH. As for the projection to the DMH, neurons in the nucleus tractus solitarius (NTS) were found to be projecting to the DMH, with 33% of those neurons being GLP-1-positive. Refeeding induced c-fos expression in the DMH projecting neurons in the NTS. Conclusion These findings suggest that GLP-1R expressing neurons in the DMH may mediate feeding termination. In addition, this meal signal may be transmitted to SCN neurons and change the neural activities.

Abstract 3426: Myostatin Deletion Preserves Cardiac Function in Senescent Mice

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Michael R Morissette ◽  
Janelle C Stricker ◽  
Anthony Rosenzweig
Keyword(s):  
Cardiac Function ◽  
Rhode Island ◽  
Cardiac Fibrosis ◽  
Physiological Role ◽  
Heart Association ◽  
Negative Regulator ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Mrna Levels ◽  
Age Related

Myostatin (MSTN) is a well-known negative regulator of skeletal muscle mass, and MSTN inhibition is being considered as therapy for multiple conditions associated with muscle wasting, including sarcopenia of aging. We have previously shown that MSTN inhibits phenylephrine-induced cardiomyocyte hypertrophy, however whether MSTN has a physiological role in regulating cardiac hypertrophy or function at baseline or with aging remains unclear. To determine if MSTN is dynamically regulated with aging, we performed QRT-PCR on hearts from male wild-type (WT) senescent mice (24 months old (mos)) and rats (32 mos). MSTN mRNA levels were increased in old versus young (4 mos) hearts (2.5- and 4-fold respectively, p<0.05). To study the functional significance of MSTN in aging, we maintained germline MSTN-knockout mice (MSTN −/− ) and their WT littermates for 24 –27 months. We found no difference in heart weight of aged male MSTN −/− compared to WT mice (162.5±17.0 (n=4) vs 153.2±4.2 (n=4) mg, p=0.51), which would argue against an inhibitory role for MSTN in age-related increases in cardiac mass. We also performed echocardiography on unanesthetized senescent MSTN −/− and WT mice. MSTN −/− mice had better fractional shortening (58.1±2.0 (n=7) vs 49.4±1.2 (n=8) %, p=0.002) and smaller LV end-diastolic diameter (3.41±0.19 vs 2.71±0.14 mm, p=0.012) compared to WT. The decreased cardiac function seen in aged WT mice was associated with increased cardiac fibrosis on Masson-Trichrome stained sections. Western blot analysis also demonstrated a 3.3-fold increase in phospholamban phosphorylation in MSTN −/− hearts (p<0.05), compared to WT, while no differences in SERCA2a or calsequestrin protein levels were seen. We conclude that MSTN increases in the heart with aging, and that genetic deletion of MSTN results in improved cardiac function without a difference in heart mass in senescent mice. Decreased cardiac fibrosis and increased inhibition (phosphorylation) of phospholamban likely contribute to the better cardiac function seen in senescent MSTN −/− mice. These results suggest that inhibiting MSTN for sarcopenia in the elderly may also benefit cardiac function and could represent a novel therapeutic approach for ameliorating cardiac dysfunction and/or fibrosis. This research has received full or partial funding support from the American Heart Association, AHA Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).

Accelerated repair of cortical bone defects using a synthetic extracellular matrix to deliver human demineralized bone matrix

2006 ◽  
Vol 24 (7) ◽  
pp. 1454-1462 ◽  
Author(s):  
Yanchun Liu ◽  
Shama Ahmad ◽  
Xiao Zheng Shu ◽  
R. Kent Sanders ◽  
Sally Anne Kopesec ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cortical Bone ◽  
Demineralized Bone Matrix ◽  
Bone Matrix ◽  
Bone Defects ◽  
Demineralized Bone

scholarly journals Gender differences in the response of CD-1 mouse bone to parathyroid hormone: potential role of IGF-I

2006 ◽  
Vol 189 (2) ◽  
pp. 279-287 ◽  
Author(s):  
Yongmei Wang ◽  
Takeshi Sakata ◽  
Hashem Z Elalieh ◽  
Scott J Munson ◽  
Andrew Burghardt ◽  
...  
Keyword(s):  
Gender Differences ◽  
Parathyroid Hormone ◽  
Cortical Bone ◽  
Mineral Apposition Rate ◽  
Mrna Levels ◽  
Male Mice ◽  
Bone Formation Rate ◽  
Male And Female ◽  
Female Mice ◽  
Igf I

Parathyroid hormone (PTH) exerts both catabolic and anabolic actions on bone. Studies on the skeletal effects of PTH have seldom considered the effects of gender. Our study was designed to determine whether the response of mouse bone to PTH differed according to sex. As a first step, we analyzed gender differences with respect to bone mass and structural properties of 4 month old PTH treated (80 μg/kg per day for 2 weeks) male and female CD-1 mice. PTH significantly increased fat free weight/body weight, periosteal bone formation rate, mineral apposition rate, and endosteal single labeling surface, while significantly decreasing medullary area in male mice compared with vehicle treated controls, but induced no significant changes in female mice. We then analyzed the gender differences in bone marrow stromal cells (BMSC) isolated from 4 month old male and female CD-1 mice following treatment with PTH (80 μg/kg per day for 2 weeks). PTH significantly increased the osteogenic colony number and the alkaline phosphatase (ALP) activity (ALP/cell) by day 14 in cultures of BMSCs from male and female mice. PTH also increased the mRNA level of receptor activator of nuclear factor κB ligand in the bone tissue (marrow removed) of both females and males. However, PTH increased the mRNA levels of IGF-I and IGF-IR only in the bones of male mice. Our results indicate that on balance a 2-weeks course of PTH is anabolic on cortical bone in this mouse strain. These effects are more evident in the male mouse. These differences between male and female mice may reflect the greater response to PTH of IGF-I and IGF-IR gene expression in males enhancing the anabolic effect on cortical bone.

scholarly journals Use of Carboxymethyl Cellulose and Collagen Carrier with Equine Bone Lyophilisate Suggests Late Onset Bone Regenerative Effect in a Humerus Drill Defect – A Pilot Study in Six Sheep

2010 ◽  
Vol 4 (1) ◽  
pp. 181-187 ◽  
Author(s):  
Jonas Jensen ◽  
Casper Bindzus Foldager ◽  
Thomas Vestergaard Jakobsen ◽  
Kjeld Søballe ◽  
Cody Bünger ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Carboxymethyl Cellulose ◽  
Late Onset ◽  
Demineralized Bone Matrix ◽  
Bone Matrix ◽  
Quantitative Computed Tomography ◽  
Drill Hole ◽  
Micro Computed Tomography ◽  
Mineral Density ◽  
Total Bone Mineral Density

We assessed the use of a filler compound together with the osteoinductive demineralized bone matrix (DBM), Colloss E. The filler was comprised of carboxymethyl-cellulose and collagen type 1. The purpose of the study was to see if the filler compound would enhance the bone formation and distribute the osteoinductive stimulus throughout the bone defect. Six sheep underwent a bilateral humerus drill defect. The drill hole was filled with a compound consisting of 100 mg CMC, 100 mg collagen powder, and 1 ccm autologous full blood in one side, and a combination of this filler compound and 20 mg Colloss E in the other. The animals were divided into three groups of two animals and observed for 8, 12 and 16 weeks. Drill holes was evaluated using quantitative computed tomography (QCT), micro computed tomography (µCT) and histomorphometry. Mean total bone mineral density (BMD) of each implantation site was calculated with both QCT and µCT. Bone volume to total volume (BV/TV) was analyzed using µCT and histomorphometry. Although not statistically significant, results showed increased bone BMD after 16 weeks in µCT data and an increased BV/TV after 16 weeks in both µCT and histology. Correlation between QCT and µCT was R2 = 0.804. Correlation between histomorphometry and µCT BV/TV data was R2 = 0.8935 and with an average overrepresentation of 8.2% in histomorphometry. In conclusion the CMC-Collagen + Colloss E filler seems like a viable osteogenic bone filler mid- to long term. A correlation was found between the analytical methods used in this study.

scholarly journals Expression patterns of endothelial and inducible nitric oxide synthase isoforms in corpora lutea of pseudopregnant rabbits at different luteal stages

2002 ◽  
Vol 173 (2) ◽  
pp. 285-296 ◽  
Author(s):  
C Boiti ◽  
D Zampini ◽  
G Guelfi ◽  
F Paolocci ◽  
M Zerani ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Expression Patterns ◽  
Physiological Role ◽  
Total Activity ◽  
Pcr Analysis ◽  
Inos Mrna ◽  
Corpora Lutea ◽  
Mrna Levels ◽  
Isolated Cells ◽  
Protein Levels

Total activity of nitric oxide (NO) synthase (NOS) and expression of both endothelial (eNOS) and inducible (iNOS) isoforms were examined in corpora lutea (CL) of rabbits across pseudopregnancy by quantitative RT-PCR analysis, Western blot and immunohistochemistry. CL were collected at early- (day 4), mid- (day 9) and late- (day 13) luteal phases of pseudopregnancy. The PCR product of rabbit luteal eNOS was cloned and its direct sequence exhibited 90% homology with those of other species. The steady-state mRNA levels encoding eNOS remained fairly constant throughout both early- and mid-luteal stages of pseudopregnancy but dropped almost to half (P</=0.05) by day 13. By contrast, luteal eNOS proteins increased 2-fold (P</=0.05) from the early- to late-luteal phase. Independently of CL age, iNOS mRNA was very poorly expressed while protein levels gradually declined from the early- to late-luteal stage. Intense eNOS-like immunoreactivity was detected in large luteal cells, while iNOS staining was targeted to a few, isolated cells, probably macrophages. Basal NOS activity was greater in day 4 CL than in both day 9 and day 13 CL. These data are the first to characterize in rabbit CL the temporal expression patterns of NOS isoforms across different luteal stages of pseudopregnancy and, collectively, suggest the existence of an expressional control for this constitutive isoform, which might have a physiological role in regulating CL function during development.

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