Age-related decreases in stimulatory G protein-coupled adenylate cyclase activity in osteoblastic cells

Donahue, Henry J.; Zhou, Zhiyi; Li, Z.; McCauley, Laurie K.

doi:10.1152/ajpendo.1997.273.4.e776

Cited by 15 publications

(20 citation statements)

References 26 publications

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“…The cAMP cascade appeared to be already activated in senescent enterocytes, as revealed by their higher basal AC activity and cAMP levels. Increased basal cAMP content during aging and related diseases has also been observed in rat osteoblasts (Donahue et al, 1997) and brain tissue (Sugawa and May, 1993). It is possible that alterations in the expression of G proteins coupling the, as yet, putative intestinal cell PTH receptor to adenylyl cyclase may occur during senescence.…”

Section: Discussionmentioning

confidence: 98%

Effect of aging on the mechanisms of PTH-induced calcium influx in rat intestinal cells

et al. 2000

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We have investigated the effects of aging on parathyroid hormone (PTH) modulation of intracellular calcium homeostasis and their relationship to signal transduction pathways in isolated rat duodenal cells (enterocytes). PTH (10(-8)-10(-9) M) increased enterocyte (45)Ca(2+) influx and intracellular Ca(2+) concentration ([Ca(2+)](i)) to a greater extent (twofold and 50%, respectively) in aged (24 months) than in young (3 months) animals. The [Ca(2+)](i) response of old cells to the hormone was slower, lacking the early phase of changes in cytosolic Ca(2+). Ca(2+) influx induced by PTH was prevented by the protein kinase A antagonist Rp-cAMPS in both young and aged enterocytes, whereas neomycin and compound U73122, inhibitors of PLC-catalyzed phosphoinositide hydrolysis, abolished hormone-dependent Ca(2+) influx in young but had no effect on aged cells. Higher basal adenylyl cyclase (AC) activity and cAMP content were detected in old enterocytes. PTH increased the absolute levels of cAMP in aged cells and AC activity of microsomes isolated therefrom to a greater extent (>/= twofold) than in young enterocytes/membranes. In young cells, the hormone also induced a rapid and transient release of inositoltrisphosphate (IP(3)) and diacylglycerol (neomycin-sensitive) at 45 sec, and a delayed phase of DAG at 5 min (neomycin-insensitive). The early formation of IP(3) and DAG was blunted in aged animals. These results suggest that both the PLC and adenylyl cyclase cascades are involved in PTH stimulation of Ca(2+) influx in duodenal cells. During aging, however, only the cAMP pathway is operative, mediating a potentiation of the effects of the hormone. Additional studies are required to establish the relative role of PTH-dependent messenger systems in the regulation of intestinal calcium absorption and age-related abnormalities.

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Section: Discussionmentioning

confidence: 98%

Effect of aging on the mechanisms of PTH-induced calcium influx in rat intestinal cells

et al. 2000

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“…Among the GPCRs in Obs, the parathyroid hormone (PTH) receptor 1 has been extensively studied and recombinant PTH has been administered to treat age- and osteoporosis-related bone loss. However, aging also results in a defect in the stimulatory G protein coupling to adenylyl cyclase, which limits the bone’s response to PTH treatment (4). PTH receptor expression and the stimulatory effects of PTH on mesenchymal stem cells also decline with aging (5).…”

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confidence: 99%

Role of Osteoblast Gi Signaling in Age-Related Bone Loss in Female Mice

et al. 2017

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Age-related bone loss is an important risk factor for fractures in the elderly; it results from an imbalance in bone remodeling mainly due to decreased bone formation. We have previously demonstrated that endogenous G protein–coupled receptor (GPCR)-driven Gi signaling in osteoblasts (Obs) restrains bone formation in mice during growth. Here, we launched a longitudinal study to test the hypothesis that Gi signaling in Obs restrains bone formation in aging mice, thereby promoting bone loss. Our approach was to block Gi signaling in maturing Obs by the induced expression of the catalytic subunit of pertussis toxin (PTX) after the achievement of peak bone mass. In contrast to the progressive cancellous bone loss seen in aging sex-matched littermate control mice, aging female Col1(2.3)+/PTX+ mice showed an age-related increase in bone volume. Increased bone volume was associated with increased bone formation at both trabecular and endocortical surfaces as well as increased bending strength of the femoral middiaphyses. In contrast, male Col1(2.3)+/PTX+ mice were not protected from age-related bone loss. Our results indicate that Gi signaling markedly restrains bone formation at cancellous and endosteal bone surfaces in female mice during aging. Blockade of the relevant Gi-coupled GPCRs represents an approach for the development of osteoporosis therapies—at least in the long bones of aging women.

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“…Furthermore, aging impairs agonist-stimulated activity of second messengers such as cAMP and Ca 2+ (14,24), and Caf + signaling has been linked to the differentiation of cells from the mesenchymal lineage (4). We found that the percentage of cells displaying spontaneous [Ca 2+ h oscillations declined with age; significantly more ROB from young rats displayed spontaneous [Ca 2+ ]i oscillations than did ROB from old rats.…”

Section: Discussionmentioning

confidence: 99%

“…We cannot rule out the possibility that the cultures contain nonosteoblastic or preosteoblastic populations. However, the ROB display an osteoblastic morphology and express phenotypic markers of osteoblasts (i.e., alkaline phosphatase, type I collagen, osteopontin, and parathyroid hormone receptor) (14,24). It is possible that age-related differences in the degree of cellular heterogeneity of our cell populations contributed to differences in responsiveness to fluid flow.…”

Section: Discussionmentioning

confidence: 99%

“…For PGE 2 and Ca 2+ experiments, bone cells were placed in a parallel plate flow chamber and subjected to oscillatory fluid flow. This system has been previously characterized, and we and others have employed it to expose endothelial cells (8), chondrocytes (37,38), and bone cells (14,15,17,41) to physiological levels of fluid flow. Briefly, the system imparts a laminar flow to the cells in a monolayer, exposing them to a shear stress governed by the equation (9) T = ß^Q/bh 2 where T is the shear stress, |x is the viscosity of the flow medium, Q is the flow rate, and b and h are the width and height of the chamber, respectively.…”

Section: Methodsmentioning

confidence: 99%

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