Bone is a dynamic organ that is known to adjust in mass, material and architectural properties with respect to the load environment. The progressive decline in muscle mass, strength/performance (sarcopenia) and bone loss (osteopenia/osteoporosis) that occurs with aging suggeste a functional coupling between the diseases. As the osteocyte is thought to be the mechanosensory cell in bone, an age-related reduction in its ability to respond to load would have significant consequences on bone mass. We have shown that the Wnt/|3-catenin signaling pathway is a critical component of bone responsiveness to mechanical loading and is rapidly activated in osteocytes following the in vivo application of load. Recent data shows that loss of one allele of P-catenin in osteocytes prevents new bone formation in response to mechanical loading. Furthermore, we have provocative preliminary data that muscle derived soluble factor(s) enhance the effecte of loading on the Wnt/p-catenin pathway in osteocytes (see Subproject 1), but that muscle converte from producing bone beneficial factors to producing bone detrimental factors with aging. This project will test the hypothesis that aging alters the osteocyte's ability to respond to mechanical loading. To test this hypothesis we propose three specific aims.
In Aim 1 we wiil determine the effect of aging on the ability of the osteocyte to respond to mechanical loading.
In Aim 2 we will determine the effect of aging on ttie osteocyte sti^in environment.
In Aim 3 we will determine in if muscle inactivation has an affect on the anabolic response of bone and whether this is latered with age.
These aims will be accomplished using young (5 mo old), mature (12 mo) and aged (22 mo) mouse models of nonmal and a new Cre mouse we have generated that allows us to temporally and specifically delete genes in osteocytes. In vitro studies using bone and muscle cell model systems and primary cells will be used to dissect the molecular basis for the changes we observe in vivo. Overall these aims will enable us to determine the magnitude of strain necessary to initiate the biological response of Wnt/p-catenin activation, whether aging alters the intrinsic ability of the osteocyte to respond to load and if the osteocyte regulates its strain environment through p-catenin expression.
The studies proposed in this project are paradigm setting and have the potential to launch a new direction for the study of musculoskeletal diseases and how aging alters these normal processes. Knowledge from these studies on how the osteocyte responds to mechanical load and how this response is conditioned by muscle derived factors will produce new targets for drug development to treat sarcopenia and osteoporosis.
|Wang, Zhiying; Bian, Liangqiao; Mo, Chenglin et al. (2017) Targeted quantification of lipid mediators in skeletal muscles using restricted access media-based trap-and-elute liquid chromatography-mass spectrometry. Anal Chim Acta 984:151-161|
|Jähn, Katharina; Kelkar, Shilpa; Zhao, Hong et al. (2017) Osteocytes Acidify Their Microenvironment in Response to PTHrP In Vitro and in Lactating Mice In Vivo. J Bone Miner Res 32:1761-1772|
|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|
|Tiede-Lewis, LeAnn M; Xie, Yixia; Hulbert, Molly A et al. (2017) Degeneration of the osteocyte network in the C57BL/6 mouse model of aging. Aging (Albany NY) 9:2190-2208|
|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|
|Maurel, Delphine B; Duan, Peipei; Farr, Joshua et al. (2016) Beta-Catenin Haplo Insufficient Male Mice Do Not Lose Bone in Response to Hindlimb Unloading. PLoS One 11:e0158381|
|Farr, Joshua N; Fraser, Daniel G; Wang, Haitao et al. (2016) Identification of Senescent Cells in the Bone Microenvironment. J Bone Miner Res 31:1920-1929|
|Gorski, Jeff P; Huffman, Nichole T; Vallejo, Julian et al. (2016) Deletion of Mbtps1 (Pcsk8, S1p, Ski-1) Gene in Osteocytes Stimulates Soleus Muscle Regeneration and Increased Size and Contractile Force with Age. J Biol Chem 291:4308-22|
|Zhu, Meiling; Sun, Ben-Hua; Saar, Katarzyna et al. (2016) Deletion of Rac in Mature Osteoclasts Causes Osteopetrosis, an Age-Dependent Change in Osteoclast Number, and a Reduced Number of Osteoblasts In Vivo. J Bone Miner Res 31:864-73|
Showing the most recent 10 out of 34 publications