FRI669 Skeletal Effect Of Cyclic Guanosine Monophosphate Dependent Protein Kinase G Type 2

Disclosure: S. Kim: None. E. Shelly: None. F. Sultana: None. F. Korkmaz: None. M. Temple: None. J. Gimenez: None. V. Muradova: None. T. Yuen: None. M. Zaidi: None. The nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway plays a significant role in bone remodeling. PKG type 2 (PKG2) is expressed in bone cells [1-2], and mice with osteoblast-specific PKG2 upregulation (Col1a1-Prkg2(R242Q)) showed increased bone formation and preserved bone in mice with streptozotocin-induced diabetes [3]. In this study, we have crossed Prkg2(fl/fl) mice with Col2.3-Cre mice and Acp5-Cre mice, respectively, to generate osteoblast-specific and osteoclast-specific Prkg2 knockout mutants. The areal BMD of osteoblast-specific or osteoclast-specific mice were not different from the respective Cre(-) controls at 4, 6 and 8 months. µCT did not show any difference in fractional bone volume (BV/TV), or trabecular parameters compared with the Cre(-) controls. However, when mice were put under skeletal insults through glucocorticoid injection (dexamethasone, 10 mg/kg, SQ, daily, 4 month), Col2.3-Cre(+);Prkg2(fl/)(+) mice lost more bone compared with Col2.3-Cre(−);Prkg2(fl/)(+) mice at the tibia (−23.1% vs. −12.1%, P=0.011). In addition, we observed the osteoblast-specific Prkg2 knockout mice displayed increased body weight (Col2.3-Cre(+);Prkg2(fl/fl) +25.1%**, Col2.3-Cre(+);Prkg2(fl/)(+) +19.9%*, Col2.3-Cre(−);Prkg2(fl/fl) +7.3%), increased fat mass (Col2.3-Cre(+);Prkg2(fl/fl) +26.0%*, Col2.3-Cre(+);Prkg2(fl/)(+) +21.4%**, Col2.3-Cre(−);Prkg2(fl/fl) −3.3%), and decreased lean mass (Col2.3-Cre(+);Prkg2(fl/fl) −4.3%*, Col2.3-Cre(+);Prkg2(fl/)(+) −2.9%, Col2.3-Cre(-);Prkg2(fl/fl) +0.3%) from the baseline (**P < 0.01 and *P < 0.05 vs. Cre(-) controls). Furthermore, we noted a longer femur length in the osteoblast-specific Prkg2 knockout mutants. At 8 months, the femur length of Col2.3-Cre(+);Prkg2(fl/fl) and Col2.3-Cre(+);Prkg2(fl/)(+) were 9.3% (P < 0.01) and 7.5% (P = 0.01), respectively, longer than the Cre(-) controls. Our findings suggest that PKG2 is necessary for protecting bone from glucocorticoid insults and abolishing PKG2 in osteoblasts might affect the differentiation of mesenchymal stem cell towards adipocytes and chondrocytes at the expense of osteoblasts and myocytes. [1] Kim et al, Ann N Y Acad Sci, 2021[2] Rangaswami J et al, Biol Chem. 2009[4] Ramdani et al, J Endocrinol 2018 Presentation: Friday, June 16, 2023