Indiana University-Purdue University Indianapolis (IUPUI) / Type 2 diabetes mellitus (T2DM) is a growing problem globally and is associated with increased
fracture risk and delayed bone healing. Novel approaches are needed in the treatment of T2DM
and the resulting diabetic osteopathy. Recent studies highlight the role of bone as an endocrine
organ producing factors that communicate with distant tissues to modulate systemic glucose
metabolism. Ca2+/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) is a potent
regulator of whole-body energy metabolism, inflammation, bone remodeling and fracture healing.
Genetic ablation of CaMKK2 protects from diet-induced obesity, insulin resistance and
inflammation, while enhancing pancreatic β cell survival and insulin secretion. Deletion or
inhibition of CaMKK2 promotes bone accrual by stimulating osteoblast-mediated bone formation
and suppressing osteoclast-mediated bone resorption; however, its specific role in osteocytes, the
master regulator of bone remodeling remains unknown. Here we demonstrate that conditional
deletion of CaMKK2 from osteocytes enhances bone mass in 3-month-old female, but not male
mice, due to suppression of osteoclasts. Conditioned media experiments and proteomics analysis
revealed that female osteocytes lacking CaMKK2 suppressed osteoclast formation and function
through enhanced secretion of calpastatin, a potent inhibitor of calpains, which are calciumdependent
cysteine proteases that support osteoclasts. Further, to determine if CaMKK2-
deficient osteocytes regulate whole-body glucose homeostasis, we placed these mice on a high-fat
diet (HFD) for a period of 16 weeks. Although the diet did not significantly impact bone mass or
strength, we found that conditional deletion of CaMKK2 in osteocytes enhanced bone
microarchitecture in 6-month-old male and female mice. We also observed that conditional
deletion of CaMKK2 from osteocytes protected male and female mice from HFD-induced obesity and insulin insensitivity. Taken together, these findings highlight CaMKK2 as a potent regulator
of osteocyte-mediated modulation of bone remodeling and whole-body energy metabolism. / 2024-08-02
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/29736 |
| Date | 07 1900 |
| Creators | Williams, Justin N. |
| Contributors | Sankar, Uma, Evans-Molina, Carmella, Bonewald, Lynda, Burr, David, Allen, Matthew |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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