Osteoclasts resorb the mineralized matrices formed by chondrocytes or osteoblasts. The cytokine receptor activator of nuclear factor-kB ligand (RANKL) is required for osteoclastogenesis and thought to be supplied by osteoblasts or their precursors, thereby linking bone formation to resorption. However, a variety of cell types can express RANKL and the identity of cells that support osteoclastogenesis remains unclear. To elucidate this question, we have deleted the RANKL gene specifically from different cell populations in vivo and demonstrated that hypertrophic chondrocytes and osteocytes, both of which are embedded in matrix, are essential sources of the RANKL that controls mineralized cartilage resorption and bone remodeling, respectively. Moreover, osteocyte RANKL is responsible for the bone loss associated with unloading and hyperparathyroidism. Contrary to the current paradigm, RANKL produced by osteoblasts or their progenitors does not contribute to bone remodeling. These results suggest that the rate-limiting step of matrix resorption is controlled by cells embedded within the matrix itself.
|Advisor:||O'Brien, Charles A.|
|Commitee:||Jilka, Robert L., Soderberg, Lee S. F, Wight, Patricia A., Zhou, Daohong|
|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:||Cellular biology, Endocrinology|
|Keywords:||Bone formation, Matrix-embedded cells, Osteoclasts, Osteocytes, RANKL|
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