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This dissertation, “Exploration of the role of serum factors in maintaining bone massduring hibernation in black bears,” is hereby approved in partial fulfillment of therequirements for the degree of DOCTOR OF PHILOSOPHY in the field of BiomedicalEngineering.DEPARTMENT:Biomedical EngineeringSignatures:Dissertation Advisor__________________________________________________Seth Donahue, PhDDateDepartment Chair__________________________________________________Sean Kirkpatrick, PhDDate
Table of contentsIndex of Figures ............................................................................................................. viiIndex of Tables ............................................................................................................... xiiAcknowledgments ......................................................................................................... xivList of Abbreviations ....................................................................................................... xvDefinitions .................................................................................................................... xviiiSpecies names .............................................................................................................. xxiAbstract ......................................................................................................................... xxiiChapter One – Background and significance ................................................................... 11.1. Problem description/significance .......................................................................... 11.2. Basics of bone remodeling ................................................................................... 21.3. Bone turnover is unbalanced during disuse ......................................................... 31.4. Osteoblast and osteocyte apoptosis results in bone loss ..................................... 31.4.1. Review of apoptosis mechanisms in osteoblasts ....................................... 41.4.2. Apoptosis precedes disuse-induced bone loss .......................................... 61.5. Disuse in humans ................................................................................................. 71.6. Disuse in non-hibernating animals ....................................................................... 81.7. Hibernation as a model of disuse ......................................................................... 91.7.1. Physiology of hibernation ......................................................................... 101.7.2. Bone response to hibernation—small hibernators.................................... 111.7.3. Bone response to hibernation—bears: histological and mechanicaldata .......................................................................................................... 121.7.4. Bone response to hibernation—bears: serum formation markers andhistomorphometry .................................................................................... 131.7.5. Hypothesis 1: BSALP and TRACP reduction during hibernation ............. 141.7.6. Hypothesis 2: OCN interacts with energy metabolism ............................. 151.7.7. Hypothesis 3: Reduced apoptotic serum factors during hibernation ........ 151.8. Hypotheses and aims ......................................................................................... 18iii
Page 1: EXPLORATION OF THE ROLE OF SERUM FA
Page 5 and 6: Chapter Four - Attempts to find an
Page 7 and 8: Index of figures1.1. Simplified sch
Page 9 and 10: 6.17. Longitudinal analysis of OPG
Page 11 and 12: 6.49. Longitudinal analysis of ColI
Page 13 and 14: A.2. Complete list of BSALP correla
Page 15 and 16: List of abbreviationsα-MEM. Alpha-
Page 17 and 18: PCR. Polymerase chain reactionPer1
Page 19 and 20: G2/M checkpoint. The point in the c
Page 21 and 22: Species names13-lined ground squirr
Page 23 and 24: Chapter One - Background and signif
Page 25 and 26: 1.3 Bone turnover is unbalanced dur
Page 27 and 28: pro-apoptosis regulator BAX. An imp
Page 29 and 30: low-dose administration of parathyr
Page 31 and 32: decrease in bone trabecular thickne
Page 33 and 34: experience periodic arousals in whi
Page 35 and 36: 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
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atios of intact to fragmented OCN m
Page 57 and 58:
Table 2.3—Bone marker “seasonal
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Table 2.7—Chemistry panel “seas
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ABNormalized BSALPBSALP (U/L)CO N D
Page 63 and 64:
Total Calcium (mg/dL)A1.21.151.11.0
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ABTotal OCN (ng/mL)150100500O N D J
Page 67 and 68:
Adiponectin (ng/mL)AB40003500300025
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ABNormalized InsulinInsulin (μU/mL
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surrounding and encompassing hibern
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decreased from 788+30 ng/mL in preh
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120-122]. Most small hibernators ar
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ears. Similarly, serum NPY increase
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Table 3.2—Serum factor longitudin
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Leptin (ng/mL)ABO N D J F M A M O N
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Norepinephrine (ng/mL)A807060504030
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IGF‐1 (ng/mL)AN D J F M A MB10009
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2008. Samples were collected as des
Page 89 and 90:
sampling points. It is possible to
Page 91 and 92:
C‐Terminal PTH (Relative)AB504030
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Chapter Five — Serum from hiberna
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Synergy HT Multi-Detection Micropla
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gene specific primers and 12.5 μL
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involved in the reduced caspase-3/7
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hibernation cycles without problem
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filtered seasonal bear serum and fo
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which is dependent upon caspase-3 a
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Caspase‐3/7 ActivityO N D J F M A
Page 109 and 110:
6Caspase‐3/7 Activity54321**0Vehi
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ABCaspase‐3/7 Activity9876543210*
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eyond the G1/S checkpoint, thus ind
Page 115 and 116:
ears, it is possible that tissue se
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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
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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
Page 139 and 140:
Cyclin D1 Gene ExpressionO N D J F
Page 141 and 142:
OPN Gene ExpressionO N D J F M A MM
Page 143 and 144:
2PTH1R Gene Expression1.510.50O N D
Page 145 and 146:
TLR4 Gene ExpressionO N D J F M A M
Page 147 and 148:
Bcl‐2 Gene ExpressionO N D J F M
Page 149 and 150:
OCN Gene ExpressionO N D J F M A MM
Page 151 and 152:
PTH1R Gene ExpressionO N D J F M A
Page 153 and 154:
TLR4 Gene ExpressionO N D J F M A M
Page 155 and 156:
condition in renal patients in whic
Page 157 and 158:
hibernation. This report brings to
Page 159 and 160:
14. Kaneps, A.J., S.M. Stover, and
Page 161 and 162:
41. Chowdhury, I., B. Tharakan, and
Page 163 and 164:
68. Ashe, M.C., et al., Bone geomet
Page 165 and 166:
95. Perrien, D.S., et al., Aging al
Page 167 and 168:
122. Lesser, R.W., et al., Renal re
Page 169 and 170:
151. Confavreux, C.B., R.L. Levine,
Page 171 and 172:
178. Toribara, T.Y., A.R. Terepka,
Page 173 and 174:
206. Luo, X.H., et al., Adiponectin
Page 175 and 176:
233. Florant, G.L., et al., Fat-cel
Page 177 and 178:
259. Bhasin, S., et al., Older men
Page 179 and 180:
284. Miura, M., et al., A crucial r
Page 181 and 182:
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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