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concentrations of melatonin were below quantifiable levels in all samples. This findingwas independently confirmed in the serum of grizzly bears, with the anatomicalobservation that the pineal gland in grizzly bears is extremely small (personalcorrespondence, Heiko Jansen).Testosterone has a decreasing trend with time in the serum of female Americanblack bears, such that the levels during post-hibernation are significantly lower than thelevels during prehibernation (Table 4.2). In contrast, previous findings demonstrateincreased testosterone in late hibernation in black bears [254-256]; however, theseprevious studies used male bears, which probably have different circannual cycles ofandrogens than females. Testosterone’s effects on bone are not fully understood. Overactivationof the androgen receptor in osteoblasts of mice increases bone turnover andreduces bone matrix quality and whole bone strength [257]. In culture, testosterone haspro-apoptotic effects on osteoblasts [258]. These two studies suggest that testosterone’sdirect effects on bone are catabolic. However, testosterone has anabolic effects ontissues which positively influence bone metabolism (e.g. muscle) [259] and is a substratefor the synthesis of estrogen, a steroid hormone with anabolic effects on bone.Therefore, testosterone may have indirect anabolic effects on bone. Indeed,testosterone has a positive correlation with femoral BMD and with serum levels of OCNand BSALP in post-menopausal women [260, 261], suggesting that testosterone maypromote bone formation in vivo. The serum levels of testosterone are not significantlydifferent during hibernation from either active season; therefore there is no evidence thattestosterone levels promote an anti-apoptotic environment during hibernation.PTH has anti-apoptotic effects on osteoblasts [49, 55], and intermittent injectionsof PTH can inhibit bone loss [56]. The Donahue lab has previously reported an increasein PTH from prehibernation through post-hibernation in bears [34]; however, thisprevious study was incomplete and limited in size. The current study has a completesample set from November through April, but includes only two bears. In another studywhich quantified PTH in the serum of 14 active and 27 hibernating American blackbears, no seasonal change in PTH was observed in non-lactating bears, though PTHwas lower in lactating than non-lactating bears [262]. In that study, there was only onesampling point in each season, in contrast to the Donahue studies which had multiple66
sampling points. It is possible to miss overall seasonal trends when only viewing onesampling point per season. A larger and more complete study must be performed beforeconclusions about seasonal PTH trends can be made. Therefore, it is unclear whetherPTH increases during hibernation, thus preventing disuse-induced osteoblast andosteocyte apoptosis. The concentrations of the c-terminal fragment of PTH were alsoquantified in the serum of hibernating and active bears. C-terminal PTH promotesosteocyte apoptosis, and inhibits bone turnover (for review see: [263]). Levels of c-terminal PTH decrease significantly during the post-hibernation season (Table 4.2).Together, the data in this study do not suggest that the serum from hibernating bearsprovides an anti-apoptotic environment for osteoblasts; however, the hormones studiedhere are only a few of many which can have effects on osteoblast apoptosis. Therefore,it would be informative to determine whether the serum from hibernating bears protectsosteoblasts from apoptosis. Such a study is reported in the following chapter.4.5 Tables and figuresTable 4.1—Summary of assaysThe number of bears and assays that were performed in each hibernation season. Thenumber of bears that gave birth to cubs is in parentheses. Unknown values are indicated as“UK.”Season Bears Age (years) Assays Data Location2006‐2007 2 (1) UKPTH, c‐terminal PTH, Figures 4.1‐4.3testosteroneTable 4.22007‐2008 4 (3) 5‐14 melatoninTable 4.2—Serum factor concentrationsData are represented as LSM+SE. The total number of samples included in the ANOVA isindicated below the mean concentrations. Letters (A, B, C) represent values that aresignificantly different from each other at α=0.05. The p-value reported is for the partial F-testfor the serum factor. “Test” represents testosterone.SerumFactorPTH(relative)C-terminalPTH(relative)Test.(ng/dL)FallWinterSpring(Active) (Hibernation) (Active)p PowerLSM+SE 12.8+3.0 15.3+2.7 14.8+4.6N samples 12 15 50.8226 0.0776LSM+SE 30.7+1.9 A 31.8+1.7 A 21.3+3.0 BN samples 12 15 50.0164 0.7493LSM+SE 54.7+7.4 A 41.2+6.6 AB 17.4+11.5 B 0.0361 0.6370N samples 45 48 3167
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EXPLORATION OF THE ROLE OF SERUM FA
Page 3 and 4:
Table of contentsIndex of Figures .
Page 5 and 6:
Chapter Four - Attempts to find an
Page 7 and 8:
Index of figures1.1. Simplified sch
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6.17. Longitudinal analysis of OPG
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6.49. Longitudinal analysis of ColI
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A.2. Complete list of BSALP correla
Page 15 and 16:
List of abbreviationsα-MEM. Alpha-
Page 17 and 18:
PCR. Polymerase chain reactionPer1
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G2/M checkpoint. The point in the c
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Species names13-lined ground squirr
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Chapter One - Background and signif
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1.3 Bone turnover is unbalanced dur
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pro-apoptosis regulator BAX. An imp
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low-dose administration of parathyr
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decrease in bone trabecular thickne
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experience periodic arousals in whi
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ears must have evolved a mechanism
Page 37 and 38: 1.7.6 Hypothesis 2: OCN interacts w
Page 39 and 40: ain, heart, and femoral muscle of h
Page 41 and 42: Hypothesis 3a: Serum concentrations
Page 44: were released. Behavior indicating
Page 47 and 48: 2.3 ResultsSerum activity of the bo
Page 49 and 50: (p
Page 51 and 52: post-hibernation sampling in the be
Page 53 and 54: also unclear whether ucOCN may affe
Page 55 and 56: atios of intact to fragmented OCN m
Page 57 and 58: Table 2.3—Bone marker “seasonal
Page 59 and 60: Table 2.7—Chemistry panel “seas
Page 61 and 62: ABNormalized BSALPBSALP (U/L)CO N D
Page 63 and 64: Total Calcium (mg/dL)A1.21.151.11.0
Page 65 and 66: ABTotal OCN (ng/mL)150100500O N D J
Page 67 and 68: Adiponectin (ng/mL)AB40003500300025
Page 69 and 70: ABNormalized InsulinInsulin (μU/mL
Page 71 and 72: surrounding and encompassing hibern
Page 73 and 74: decreased from 788+30 ng/mL in preh
Page 75 and 76: 120-122]. Most small hibernators ar
Page 77 and 78: ears. Similarly, serum NPY increase
Page 79 and 80: Table 3.2—Serum factor longitudin
Page 81 and 82: Leptin (ng/mL)ABO N D J F M A M O N
Page 83 and 84: Norepinephrine (ng/mL)A807060504030
Page 85 and 86: IGF‐1 (ng/mL)AN D J F M A MB10009
Page 87: 2008. Samples were collected as des
Page 91 and 92: C‐Terminal PTH (Relative)AB504030
Page 93 and 94: Chapter Five — Serum from hiberna
Page 95 and 96: Synergy HT Multi-Detection Micropla
Page 97 and 98: gene specific primers and 12.5 μL
Page 99 and 100: involved in the reduced caspase-3/7
Page 101 and 102: hibernation cycles without problem
Page 103 and 104: filtered seasonal bear serum and fo
Page 105 and 106: which is dependent upon caspase-3 a
Page 107 and 108: Caspase‐3/7 ActivityO N D J F M A
Page 109 and 110: 6Caspase‐3/7 Activity54321**0Vehi
Page 111 and 112: ABCaspase‐3/7 Activity9876543210*
Page 113 and 114: eyond the G1/S checkpoint, thus ind
Page 115 and 116: ears, it is possible that tissue se
Page 117 and 118: PTH1R, RANKL, Runx2, Smurf1, TLR4,
Page 119 and 120: factors Runx2 and OCN also increase
Page 121 and 122: Table 6.3—Gene expression 3 hour
Page 123 and 124: Table 6.5—Gene expression 6 day d
Page 125 and 126: Cyclin D1 Gene ExpressionO N D J F
Page 127 and 128: Smurf1 Gene ExpressionO N D J F M A
Page 129 and 130: BAK Gene ExpressionO N D J F M A MM
Page 131 and 132: M‐CSF Gene ExpressionO N D J F M
Page 133 and 134: Per1 Gene ExpressionO N D J F M A M
Page 135 and 136: Akt Gene ExpressionO N D J F M A MM
Page 137 and 138: Bcl‐2 Gene ExpressionO N D J F M
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Cyclin D1 Gene ExpressionO N D J F
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OPN Gene ExpressionO N D J F M A MM
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2PTH1R Gene Expression1.510.50O N D
Page 145 and 146:
TLR4 Gene ExpressionO N D J F M A M
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Bcl‐2 Gene ExpressionO N D J F M
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OCN Gene ExpressionO N D J F M A MM
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PTH1R Gene ExpressionO N D J F M A
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TLR4 Gene ExpressionO N D J F M A M
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condition in renal patients in whic
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hibernation. This report brings to
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14. Kaneps, A.J., S.M. Stover, and
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41. Chowdhury, I., B. Tharakan, and
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68. Ashe, M.C., et al., Bone geomet
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95. Perrien, D.S., et al., Aging al
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122. Lesser, R.W., et al., Renal re
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151. Confavreux, C.B., R.L. Levine,
Page 171 and 172:
178. Toribara, T.Y., A.R. Terepka,
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206. Luo, X.H., et al., Adiponectin
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233. Florant, G.L., et al., Fat-cel
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259. Bhasin, S., et al., Older men
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284. Miura, M., et al., A crucial r
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Appendix A—Complete tables of cor
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Table A.5—Complete list of ionize
Page 185 and 186:
Table A.7—Complete list of adipon
Page 187 and 188:
Table A.12—Complete list of norep
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