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EXPERIMENT INFORMATION

Role of Marrow Adipocytes in Bone Loss during Simulated Spaceflight (NNX12AL24G)
Principal Investigator
Research Area:
Cell and molecular biology
Species Studied
Scientific Name: Mus musculus Species: Mouse

Description
OBJECTIVES:
Space flight, by impairing the differentiation program of stem cells residing within bone marrow results in bone loss, increased bone marrow adiposity, anemia, and impaired immune function. Because these disturbances may potentially compromise the success of long-duration flights, there exists an urgent need to identify the underlying mechanisms and implement effective countermeasures. This experiment will test the novel hypothesis that negative energy balance during space flight results in 1) bone marrow dysfunction and increased marrow adiposity and 2) altered signaling by peripheral adipokines (cytokines produced by adipocytes) all of which, in turn, contribute to negative bone turnover balance and bone loss. The proposed research will focus on the precise role of adipose tissue and the important adipokine leptin in mediating the detrimental effects of simulated spaceflight (hindlimb unloading) on bone marrow cells in mice by accomplishing the following 2 specific aims: Specific Aim 1 will test the hypothesis that increased bone marrow adiposity plays a causal role in mediating simulated space flight-induced changes in bone metabolism. This will be accomplished by comparing the skeletal response to hindlimb unloading of wild type (WT) mice with mice incapable of generating bone marrow adipocytes (kit-receptor-deficient KitW/W-v mice). Specific Aim 2 will test the hypothesis that the adipokine leptin, by targeting the differentiation of bone marrow stem cells, plays a key role in mediating energy sensitive changes in bone metabolism during simulated spaceflight. This will be accomplished by examining whether transplantation of mesenchymal or hematopoietic stem cells from leptin receptor-deficient db/db mice into WT mice alters bone loss during simulated space flight. Completion of the proposed project is expected to increase our understanding of the role of energy metabolism in mediating bone loss during simulated space flight and suggest specific non-pharmacological and pharmacological interventions to mitigate the detrimental effects of space flight on bone marrow.


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Publications
Turner RT, Iwaniec UT, Wong CP, Lindenmaier LB, Wagner LA, Branscum AJ, Menn SA, Taylor J, Zhang Y, Wu H, and Sibonga JD. Acute exposure to high dose ?-radiation results in transient activation of bone lining cells. Bone. 2013. November; 57(1):164-73. [pubmed.gov]

Turner RT, Philbrick KA, Wong CP, Olson DA, Branscum AJ, Iwaniec UT. Morbid obesity attenuates the skeletal abnormalities associated with leptin deficiency in mice. Journal of Endocrinology. 2014. October; 223(1):M1-15. [pubmed.gov]

Keune JA, Branscum AJ, Iwaniec UT, Turner RT. Effects of spaceflight on bone microarchitecture in the axial and appendicular skeleton in growing ovariectomized rats. Sci Rep. 2015 Dec 22;5:18671. pubmed.gov

Iwaniec UT, Turner RT. Influence of body weight on bone mass, architecture, and turnover. J Endocrinol. 2016 Sep. 230(3):R115-30. pubmed.gov

Keune JA, Philbrick KA, Branscum AJ, Iwaniec UT, Turner RT. Spaceflight-induced vertebral bone loss in ovariectomized rats is associated with increased bone marrow adiposity and no change in bone formation. npj Microgravity. npj 2, Article number: 16016 (2016). [DOI]

Iwaniec, Urszula T., and Russell T. Turner. “Failure to Generate Bone Marrow Adipocytes Does Not Protect Mice from Ovariectomy-Induced Osteopenia.” Bone 2013 Mar;53(1):145-53. [DOI]

Philbrick KA, Turner RT, Branscum AJ, Wong CP, Iwaniec UT. Paradoxical effects of partial leptin deficiency on bone in growing female mice. Anat Rec 2015 Dec;298(12):2018-29. pubmed.gov

Lindenmaier LB, Philbrick KA, Branscum AJ, Kalra SP, Turner RT, Iwaniec UT. Hypothalamic leptin gene therapy reduces bone marrow adiposity in ob/ob mice fed regular and high-fat diets. Front Endocrinol (Lausanne). 2016 Aug 16;7:110. pubmed.gov

Philbrick KA, Wong CP, Branscum AJ, Turner RT, Iwaniec UT. Leptin stimulates bone formation in ob/ob mice at doses having minimal impact on energy metabolism. J Endocrinol. 2017 Jan 5. pubmed.gov [DOI]

Keune, J.A.; Wong, C.P.; Branscum, A.J.; Iwaniec, U.T.; Turner, R.T.: Bone Marrow Adipose Tissue Deficiency Increases Disuse-Induced Bone Loss in Male Mice. 2017. Scientific Reports 7, Article number: 46325. [DOI]

Turner RT, Philbrick KA, Kuah A, Branscum AJ, Iwaniec UT. Role of oestrogen receptor signaling in skeletal response to leptin in female ob/ob mice. J Endocrinol. 2017 Apr 20. [Epub ahead of print] pubmed.gov

Philbrick KA, Martin SA, Colagiovanni AR, Branscum AJ, Turner RT, Iwaniec UT. Effects of hypothalamic leptin gene therapy on osteopetrosis in leptin-deficient mice. J Endocrinol. 2017 Nov 30. pubmed.gov [DOI]

Turner RT, Martin SA, Iwaniec UT. Metabolic coupling between bone marrow adipose tissue and hematopoiesis. Curr Osteoporos Rep. 2018 Feb 28. pubmed.gov [DOI]

Deyhle RT Jr, Wong CP, Martin SA, McDougall MQ, Olson DA, Branscum AJ, Menn SA, Iwaniec UT, Hamby DM, Turner RT.Maintenance of near normal bone mass and architecture in lethally irradiated female mice following adoptive transfer with as few as 750 purified hematopoietic stem cells. Radiat Res. 2019 Mar 14. pubmed.gov [DOI]

Keune JA, Branscum AJ, Wong CP, Iwaniec UT, Turner RT. Effect of leptin deficiency on the skeletal response to hindlimb unloading in adult male mice. Sci Rep. 2019 Jun 27;9(1):9336. pubmed.gov [DOI]

Keywords
Blood glucose
Bone and bones
Bone density
Bone marrow cells
Diaphyses
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Data Information
Data Availability
Archive is complete. Some data sets are online.
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Some data sets are not publicly available but can be requested.
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Parameters
blood glucose
Body mass
connectivity density
femur bone volume
Seminal vesicle weight
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Mission/Study Information
Mission Launch/Start Date Landing/End Date Duration
Ground 05/01/2009 In Progress

Additional Information
Managing NASA Center
Ames Research Center (ARC)
Responsible NASA Representative
Ames Research Center LSDA Level 3
Project Manager: Martha Del Alto
Institutional Support
National Aeronautics and Space Administration (NASA)
Proposal Date
09/15/2012
Proposal Source
2011 Space Biology NNH11Z