Effects on bone by the light/dark cycle and chronic treatment with melatonin and/or hormone replacement therapy in intact female mice.
In this study, the effects of the light/dark cycle, hormone replacement therapy (HRT), and nocturnal melatonin supplementation on osteogenic markers and serum melatonin levels were examined in a blind mouse model (MMTV-Neu transgenic mice). Melatonin levels in this mouse strain (FVB/N) with retinal degeneration (rd-/-) fluctuate in a diurnal manner, suggesting that these mice, although blind, still perceive light. Real-time RT-PCR analyses demonstrated that Runx2, Bmp2, Bmp6, Bglap, and Per2 mRNA levels coincide with melatonin levels. The effect of chronic HRT (0.5 mg 17β-estradiol + 50 mg progesterone in 1800 kcal of diet) alone and in combination with melatonin (15 mg/L drinking water) on bone quality and density was also assessed by histomorphometry and microcomputed tomography, respectively. Bone density was significantly increased (P < 0.05) after 1 yr of treatment with the individual therapies, HRT (22% increase) and nocturnal melatonin (20% increase) compared to control. Hormone replacement therapy alone also increased surface bone, decreased trabecular space, and decreased the number of osteoclasts without affecting osteoblast numbers compared to the control group (P < 0.05). Chronic HRT + melatonin therapy did not significantly increase bone density, even though this combination significantly increased Bglap mRNA levels. These data suggest that the endogenous melatonin rhythm modulates markers important to bone physiology. Hormone replacement therapy with or without nocturnal melatonin in cycling mice produces unique effects on bone markers and bone density. The effects of these therapies alone and combined may improve bone health in women in perimenopause and with low nocturnal melatonin levels from too little sleep, too much light, or age.
Division of Pharmaceutical Sciences, School of Pharmacy, Duquesne University, Pittsburgh, PA 15282, USA. wittp@duq.edu
Paula A
PA
Witt-Enderby
John P
JP
Slater
Nakpangi A
NA
Johnson
Corry D
CD
Bondi
Balasunder R
BR
Dodda
Mary P
MP
Kotlarczyk
William P
WP
Clafshenkel
Shalini
S
Sethi
Suzanne
S
Higginbotham
James L
JL
Rutkowski
Katie M
KM
Gallagher
Vicki L
VL
Davis
D000818:Animals; D015519:Bone Density / Q000187:drug effects / Q000528:radiation effects; D050071:Bone Density Conservation Agents / Q000008:administration & dosage*; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism; D055418:Bone Morphogenetic Protein 6 / Q000235:genetics / Q000378:metabolism; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D002940:Circadian Rhythm / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004958:Estradiol / Q000008:administration & dosage*; D015914:Estrogen Replacement Therapy; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D008550:Melatonin / Q000008:administration & dosage* / Q000097:blood; D051379:Mice; D008822:Mice, Transgenic; D015675:Osteocalcin / Q000235:genetics / Q000378:metabolism; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism; D017440:Photoperiod; D011374:Progesterone / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D055114:X-Ray Microtomography
D050071:Bone Density Conservation Agents; D055396:Bone Morphogenetic Protein 2; D055418:Bone Morphogenetic Protein 6; D050659:Core Binding Factor Alpha 1 Subunit; D004958:Estradiol; D008550:Melatonin; D015675:Osteocalcin; D056950:Period Circadian Proteins; D011374:Progesterone; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; C525719:Bmp2 protein, mouse; C525817:Bmp6 protein, mouse; C513312:Per2 protein, mouse; C493716:Runx2 protein, mouse; C483804:Erbb2 protein, rat