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1.
JCI Insight ; 9(14)2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38885330

RESUMO

Osteoporotic fractures are a major complication of long-term glucocorticoid therapy. Glucocorticoids transiently increase bone resorption, but they predominantly inhibit bone formation and induce osteocyte apoptosis, leading to bone loss. Current treatments of glucocorticoid-induced osteoporosis aim mainly at reducing bone resorption and are, therefore, inadequate. We previously showed that signaling via the NO/cGMP/protein kinase G pathway plays a key role in skeletal homeostasis. Here, we show that pharmacological PKG activation with the guanylyl cyclase-1 activator cinaciguat or expression of a constitutively active, mutant PKG2R242Q restored proliferation, differentiation, and survival of primary mouse osteoblasts exposed to dexamethasone. Cinaciguat treatment of WT mice or osteoblast-specific expression of PKG2R242Q in transgenic mice prevented dexamethasone-induced loss of cortical bone mass and strength. These effects of cinaciguat and PKG2R242Q expression were due to preserved bone formation parameters and osteocyte survival. The basis for PKG2's effects appeared to be through recovery of Wnt/ß-catenin signaling, which was suppressed by glucocorticoids but critical for proliferation, differentiation, and survival of osteoblast-lineage cells. Cinaciguat reduced dexamethasone activation of osteoclasts, but this did not occur in the PKG2R242Q transgenic mice, suggesting a minor role in osteoprotection. We propose that existing PKG-targeting drugs could represent a novel therapeutic approach to prevent glucocorticoid-induced osteoporosis.


Assuntos
Proteínas Quinases Dependentes de GMP Cíclico , Dexametasona , Glucocorticoides , Camundongos Transgênicos , Osteoblastos , Osteoporose , Via de Sinalização Wnt , Animais , Osteoporose/induzido quimicamente , Osteoporose/metabolismo , Osteoporose/patologia , Camundongos , Glucocorticoides/efeitos adversos , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Dexametasona/farmacologia , Dexametasona/efeitos adversos , Via de Sinalização Wnt/efeitos dos fármacos , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Diferenciação Celular/efeitos dos fármacos , Osteócitos/metabolismo , Osteócitos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Proliferação de Células/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos
2.
JACC Basic Transl Sci ; 9(1): 46-62, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38362350

RESUMO

Major pathologic changes in the proximal aorta underlie the life-threatening aortic aneurysms and dissections in Marfan Syndrome; current treatments delay aneurysm development without addressing the primary pathology. Because excess oxidative stress and nitric oxide/protein kinase G signaling likely contribute to the aortopathy, we hypothesized that cobinamide, a strong antioxidant that can attenuate nitric oxide signaling, could be uniquely suited to prevent aortic disease. In a well-characterized mouse model of Marfan Syndrome, cobinamide dramatically reduced elastin breaks, prevented excess collagen deposition and smooth muscle cell apoptosis, and blocked DNA, lipid, and protein oxidation and excess nitric oxide/protein kinase G signaling in the ascending aorta. Consistent with preventing pathologic changes, cobinamide diminished aortic root dilation without affecting blood pressure. Cobinamide exhibited excellent safety and pharmacokinetic profiles indicating it could be a practical treatment. We conclude that cobinamide deserves further study as a disease-modifying treatment of Marfan Syndrome.

3.
J Bone Miner Res ; 38(1): 171-185, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36371651

RESUMO

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/ß-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/ß-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/ß-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).


Assuntos
Osso e Ossos , beta Catenina , Feminino , Animais , Camundongos , Masculino , beta Catenina/metabolismo , Osso e Ossos/metabolismo , Osteoblastos/metabolismo , Osteogênese , Camundongos Knockout , Via de Sinalização Wnt , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Homeostase
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