A decline in estrogen levels, such as occurs at the menopause, causes bone loss by increasing the number of bone resorbing osteoclasts. The mechanisms by which estrogen controls osteoclast number are only partially understood, but previous studies suggest that lymphocytes play an important role. For example, ovariectomy of mice or rats consistently leads to increased numbers of B lymphocytes in the bone marrow. This increase in B cell number has been suggested to contribute to increased osteoclast formation by different mechanisms, such as B cell production of the osteoclastogenic cytokine receptor activator of NF-kappa-B ligand (RANKL) and differentiation of B cell precursors into osteoclasts. However, until recently, there was no functional evidence that B cells play an essential role in ovariectomy-induced bone loss. In studies leading to this application, we have found that production of the cytokine receptor activator of NF-kappa-B ligand (RANKL) by B lymphocytes is essential for the cancellous bone loss caused by estrogen deficiency in mice. Importantly, RANKL is also required for the increase in B cell number that is caused by estrogen deficiency. Also, ovariectomy did not increase the levels of RANKL in B cells in wild type mice. Together, these results suggest that it is the increase in B cell number that is required for ovariectomy-induced bone loss in this model. It is also important to note that deletion of RANKL from B cells did not prevent loss of cortical bone caused by estrogen deficiency. Therefore, RANKL produced by cell types other than B cells must be involved in the osteoclast formation in this skeletal compartment. Based on these results, we hypothesize that loss of estrogen causes cancellous bone loss, in part, by increasing the number of B cells, which can then act as osteoclast progenitors. Further, we propose that loss of estrogen causes cortical bone loss by altering production of RANKL by cells of the osteoblast lineage. To address these hypotheses, lineage-tracing studies will be performed to determine whether B cells, at any stage of their development, can differentiate into bone resorbing osteoclasts in vivo. In addition, whether estrogen suppresses B cell number by acting directly on these cells will be determined by conditional deletion of estrogen receptor alpha from this cell type. Lastly, mice in which the RANKL gene has been deleted from either osteocytes or from stromal cells of the osteoblast lineage will be ovariectomized to determine whether RANKL produced by these cell types contributes to the cortical bone loss caused by estrogen deficiency.
Estrogen deficiency causes bone loss in females and may contribute to loss of bone in males. However, the cellular and molecular mechanisms by which estrogen protects the skeleton are not well understood. The work proposed in this application will investigate how immune cells known as B lymphocytes contribute to bone resorption during estrogen deficiency and whether cytokine production by cells of the osteoblast lineage also contributes to bone loss in this condition.
|O'Brien, Charles A; Morello, Roy (2018) Modeling Rare Bone Diseases in Animals. Curr Osteoporos Rep 16:458-465|
|Xiong, Jinhu; Almeida, Maria; O'Brien, Charles A (2018) The YAP/TAZ transcriptional co-activators have opposing effects at different stages of osteoblast differentiation. Bone 112:1-9|
|Weinstein, Robert S; Hogan, Erin A; Borrelli, Michael J et al. (2017) The Pathophysiological Sequence of Glucocorticoid-Induced Osteonecrosis of the Femoral Head in Male Mice. Endocrinology 158:3817-3831|
|Piemontese, Marilina; Almeida, Maria; Robling, Alexander G et al. (2017) Old age causes de novo intracortical bone remodeling and porosity in mice. JCI Insight 2:|
|Piemontese, Marilina; Xiong, Jinhu; Fujiwara, Yuko et al. (2016) Cortical bone loss caused by glucocorticoid excess requires RANKL production by osteocytes and is associated with reduced OPG expression in mice. Am J Physiol Endocrinol Metab 311:E587-93|
|Fujiwara, Yuko; Piemontese, Marilina; Liu, Yu et al. (2016) RANKL (Receptor Activator of NF?B Ligand) Produced by Osteocytes Is Required for the Increase in B Cells and Bone Loss Caused by Estrogen Deficiency in Mice. J Biol Chem 291:24838-24850|
|Piemontese, Marilina; Onal, Melda; Xiong, Jinhu et al. (2016) Low bone mass and changes in the osteocyte network in mice lacking autophagy in the osteoblast lineage. Sci Rep 6:24262|
|Xiong, Jinhu; Piemontese, Marilina; Onal, Melda et al. (2015) Osteocytes, not Osteoblasts or Lining Cells, are the Main Source of the RANKL Required for Osteoclast Formation in Remodeling Bone. PLoS One 10:e0138189|
|Piemontese, Marilina; Onal, Melda; Xiong, Jinhu et al. (2015) Suppression of autophagy in osteocytes does not modify the adverse effects of glucocorticoids on cortical bone. Bone 75:18-26|
|Xiong, Jinhu; Piemontese, Marilina; Thostenson, Jeff D et al. (2014) Osteocyte-derived RANKL is a critical mediator of the increased bone resorption caused by dietary calcium deficiency. Bone 66:146-54|
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