The cytokine receptor activator of NFκB ligand (RANKL) is irreplaceable for osteoclast formation and function. Increased RANKL expression by different cell populations is thought to increase osteoclast numbers during altered hormonal status and inflammation. Therefore we examined bone loss caused by changes in hormonal status or inflammation in mouse models in which either the increase in RANKL was blunted or RANKL was deleted from specific cell populations. Deletion of a transcriptional enhancer known as the DCR prevented the increase in RANKL caused by either secondary hyperparathyroidism or lactation but did not prevent bone loss. In contrast, deletion of the RANKL gene from B lymphocytes blunted the bone loss caused by either ovariectomy or LPS-induced inflammation. These results demonstrate that increases in RANKL expression are not always required for hormone-induced bone loss, likely due to redundant mechanisms for stimulating osteoclast differentiation. On the other hand, RANKL expression in specific cell types, such as B lymphocytes, contributes significantly to the bone loss caused by loss of estrogen or by systemic inflammation.
|Advisor:||O'Brien, Charles A.|
|Commitee:||Jilka, Robert L., Kelly, Thomas J., Reis, Robert R.J., Rusch, Nancy J.|
|School:||University of Arkansas for Medical Sciences|
|Department:||Interdisciplinary Biomedical Sciences|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 74/06(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Cellular biology, Endocrinology|
|Keywords:||Bone, Calcium homeostasis, Inflammation, Osteoclast, Rankl, Sex steroids|
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