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Protein Kinase G2 Is Essential for Skeletal Homeostasis and Adaptation to Mechanical Loading in Male but Not Female Mice |
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| Authors: | Hema Kalyanaraman Shyamsundar Pal China Justin A Cabriales Jafar Moininazeri Darren E Casteel Julian J Garcia Van W Wong Albert Chen Robert L Sah Gerry R Boss Renate B Pilz |
| Institution: | 1. Department of Medicine, University of California, San Diego, La Jolla, CA, USA
Contribution: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Supervision, Writing - original draft;2. Department of Medicine, University of California, San Diego, La Jolla, CA, USA Contribution: Data curation, Formal analysis, Investigation, Methodology, Software;3. Department of Medicine, University of California, San Diego, La Jolla, CA, USA Contribution: Investigation, Methodology;4. Department of Medicine, University of California, San Diego, La Jolla, CA, USA Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA Contribution: Methodology, Software;5. Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA Contribution: Methodology, Software;6. Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA Contribution: Data curation, Software;7. Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA Contribution: Conceptualization, Methodology, Software, Writing - review & editing;8. Department of Medicine, University of California, San Diego, La Jolla, CA, USA Contribution: Conceptualization, Funding acquisition, Supervision, Writing - review & editing;9. Department of Medicine, University of California, San Diego, La Jolla, CA, USA |
| Abstract: | We previously showed that the NO/cGMP/protein kinase G (PKG) signaling pathway positively regulates osteoblast proliferation, differentiation, and survival in vitro, and that cGMP-elevating agents have bone-anabolic effects in mice. Here, we generated mice with an osteoblast-specific (OB) knockout (KO) of type 2 PKG (gene name Prkg2) using a Col1a1(2.3 kb)-Cre driver. Compared to wild type (WT) littermates, 8-week-old male OB Prkg2-KO mice had fewer osteoblasts, reduced bone formation rates, and lower trabecular and cortical bone volumes. Female OB Prkg2-KO littermates showed no bone abnormalities, despite the same degree of PKG2 deficiency in bone. Expression of osteoblast differentiation- and Wnt/β-catenin-related genes was lower in primary osteoblasts and bones of male KO but not female KO mice compared to WT littermates. Osteoclast parameters were unaffected in both sexes. Since PKG2 is part of a mechano-sensitive complex in osteoblast membranes, we examined its role during mechanical loading. Cyclical compression of the tibia increased cortical thickness and induced mechanosensitive and Wnt/β-catenin-related genes to a similar extent in male and female WT mice and female OB Prkg2-KO mice, but loading had a minimal effect in male KO mice. We conclude that PKG2 drives bone acquisition and adaptation to mechanical loading via the Wnt/β-catenin pathway in male mice. The striking sexual dimorphism of OB Prkg2-KO mice suggests that current U.S. Food and Drug Administration-approved cGMP-elevating agents may represent novel effective treatment options for male osteoporosis. © 2022 American Society for Bone and Mineral Research (ASBMR). |
| Keywords: | ANALYSIS—OTHER (MECHANICAL LOADING) GENETIC ANIMAL MODEL MOLECULAR PATHWAYS—REMODELING OSTEOBLASTS WNT/β-CATENIN |