Indiana University-Purdue University Indianapolis (IUPUI) / Old age is associated with increased bone fragility and risk of fracture as a result
of skeletal alterations, including low bone density and cortical thinning. Further, apoptotic
osteocytes accumulate in old mice and humans. We have previously shown that mice
lacking osteocytic connexin (Cx) 43 (Cx43ΔOt) exhibit a phenotype similar to that of the
aging skeleton, with elevated osteocyte apoptosis and an associated increase in
osteoclastogenesis. These findings suggest that osteocyte apoptosis results in the release
of factors that recruit osteoclasts to bone surfaces close to areas that contain apoptotic
osteocytes. However, the specific chemotactic signals, the events mediating their release,
and the mechanisms of their action remain unknown. Consistent with this notion, we also
found that HMGB1 released by Cx43-deficient (Cx43def) MLO-Y4 osteocytic cells
enhances osteoclastogenesis in part by increasing osteocytic RANKL, which promotes
osteoclastogenesis, and, at the same time, directly stimulating osteoclastogenesis.
Further, expression of the pro-survival microRNA (miR), miR21, is low in Cx43def cells and
bones from old female mice, and low miR21 levels increase osteocyte apoptosis.
However, surprisingly, mice lacking miR21 (miR21ΔOt) have decreased osteoclast number
and activity even under conditions of elevated osteocyte apoptosis; suggesting that
osteocytic miR21 may mediate osteoclast precursor recruitment/survival induced by
apoptotic osteocytes. However, whether HMGB1/miR21 are released by osteocytes, and
if the HMGB1 receptors, receptor for advanced glycation end products (RAGE) and/or tolllike
receptor (TLR4) are involved in osteoclast recruitment in Cx43ΔOt and old mice is
unknown. The overall objectives of this series of studies were to elucidate the mechanisms
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/19949 |
| Date | 06 1900 |
| Creators | Davis, Hannah Marie |
| Contributors | Plotkin, Lillian I., Bidwell, Joseph P., Allen, Matthew R., Bruzzaniti, Angela |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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