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Open Access Publications from the University of California

Scholarly Works (3 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2021)

Bone fractures are a major cause of morbidity and mortality, particularly in patients with diabetes, who have a high incidence of fractures and exhibit poor fracture healing. The NO/cGMP/protein kinase G (PKG) signaling pathway mediates osteoblast response to estrogens and mechanical stimulation, and is downregulated in diabetes by a defective enzyme, soluble guanylate cyclase (sGC). Here, we used a mouse mono-cortical defect model to stimulate bone regeneration in diabetic and non-diabetic mice which were treated with either vehicle or a NO-independent activator of oxidized sGC, cinaciguat. Diabetic mice demonstrated low Vegfa and Bmp2/4 expression in bone and impaired bone regeneration after injury; notably, the cGMP-elevating agent cinaciguat restored Vegfa and Bmp2/4 expression, full bone healing, but had no effect on mechanical properties of uninjured bone in the diabetic animals, likely due to the short treatment duration. We conclude that PKG1 is a key orchestrator of VEGF and BMP signaling during bone regeneration and propose pharmacological PKG activation as a novel therapeutic approach to enhance fracture healing.

    Cover page: Protein Kinase G1 Activation Improves Diabetic Fracture Healing
    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2015)
    Postsurgical cardiac adhesions increase the number of surgeries as well as patient mortality and morbidity. A fast gelling oxime-crosslinked PEG hydrogel with tunable gelation time, degradation, and mechanical properties is presented. This material is cytocompatible and prevents cellular adhesion. Material retention on different cardiac tissues is demonstrated ex vivo over time and that functional group ratio alters material retention on different cardiac tissues.
      Cover page: Binding of Anticell Adhesive Oxime‐Crosslinked PEG Hydrogels to Cardiac Tissues
      • Article
      • Peer Reviewed
      UC San Diego Previously Published Works (2023)
      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).
        Cover page: Protein Kinase G2 Is Essential for Skeletal Homeostasis and Adaptation to Mechanical Loading in Male but Not Female Mice.
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