Osteoporosis and Sarcopenia are diseases of bone and muscle loss that represent a major clinical problem in the aged population. These conditions often occur together, suggesting common pathogenic mechanisms and/or crosstalk between muscle and bone. Current treatment for osteoporosis target osteoclast or osteoblast activity to maintain bone mass, but the osteocyte has been overlooked. Exciting recent research has shown that osteocytes are major regulators of osteoblast and osteoclast function and that regulation of the Wnt/3-catenin pathway by osteocytes may play a central role in regulation of bone mass. Our laboratory has taken a unique approach to examining osteoblast-osteocyte interactions using fluorescence live imaging approaches in bone cell and organ culture models. We have shown that osteoblasts on the bone surface are motile cells and that assembly of ECM proteins In living osteoblasts is a highly dynamic process that is integrated with cell motility. We have also shown that Sclerostin and Wnts, both produced by osteocytes, can alter osteoblast motility and differentiated function. Building on these observations, this project will examine osteocyte control of osteoblast function from a dynamic perspective. The overall hypothesis is that osteocytes regulate bone mass through the Wnt/p-catenin signaling pathway by controlling the motile properties and differentiated function of osteoblasts and that this regulatory process is modulated by muscle- bone crosstalk and is impaired during aging, leading to a compromised skeleton. To address this hypothesis, live cell imaging techniques will be used in young and aged transgenic mouse models expressing fluorescent reporters for osteoblast and osteocyte lineages and GFP-tagged extracellular matrix proteins. The effect of modulation of osteocyte-produced Wnt and sclerostin will be investigated using inhibitors, gene silencing and transgenic approaches. To determine whether crosstalk from muscle alters osteocyte control of osteoblast function, in viti-o models of myoblast differentiation and transgenic and aged models of impaired or enhanced muscle function will be used. These studies may lead to the way to novel therapeutic approaches for preventing loss of bone and muscle mass in the elderly.

Public Health Relevance

Osteoporosis and sarcopenia are diseases of bone and muscle loss that often occur together in the aged population and represent a major public health problem. The goal of this research is to determine the molecular and cellular mechanisms that contribute to the coordinated development of these conditions. This research may lead to development of new treatment approaches for these diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG039355-02
Application #
8460479
Study Section
Special Emphasis Panel (ZAG1-ZIJ-9)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$244,956
Indirect Cost
$81,651
Name
University of Missouri Kansas City
Department
Type
DUNS #
010989619
City
Kansas City
State
MO
Country
United States
Zip Code
64110
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Pin, Fabrizio; Barreto, Rafael; Kitase, Yukiko et al. (2018) Growth of ovarian cancer xenografts causes loss of muscle and bone mass: a new model for the study of cancer cachexia. J Cachexia Sarcopenia Muscle 9:685-700
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Huang, Jian; Romero-Suarez, Sandra; Lara, Nuria et al. (2017) Crosstalk between MLO-Y4 osteocytes and C2C12 muscle cells is mediated by the Wnt/?-catenin pathway. JBMR Plus 1:86-100
Bonewald, Lynda F (2017) The Role of the Osteocyte in Bone and Nonbone Disease. Endocrinol Metab Clin North Am 46:1-18
Vemula, Harika; Kitase, Yukiko; Ayon, Navid J et al. (2017) Gaussian and linear deconvolution of LC-MS/MS chromatograms of the eight aminobutyric acid isomers. Anal Biochem 516:75-85

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