cAMP/PKA Signaling Inhibits Osteogenic Differentiation and Bone Formation in Rodent Models

Siddappa, Ramakrishnaiah; Mulder, Winfried R.; Steeghs, Ilse; Klundert, Christine van de; Fernandes, Hugo; Li, Jun; Arends, Roel; Blitterswijk, Clemens A. van; Boer, Jan de

doi:10.1089/ten.tea.2008.0512

Cited by 44 publications

(36 citation statements)

References 58 publications

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“…These data may help in growing these cells ex vivo and explain some of the inconsistencies noted by investigators on cAMP signaling and growth of mesenchymal cells (47,(49)(50)(51). The present data are also helpful in understanding better the process of malignant transformation for which BSCs and other pluripotential cells are at risk (52).…”

Section: Discussionmentioning

confidence: 53%

Alternate protein kinase A activity identifies a unique population of stromal cells in adult bone

Tsang

Starost

Nesterova

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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A population of stromal cells that retains osteogenic capacity in adult bone (adult bone stromal cells or aBSCs) exists and is under intense investigation. Mice heterozygous for a null allele of prkar1a (Prkar1a +/− ), the primary receptor for cyclic adenosine monophosphate (cAMP) and regulator of protein kinase A (PKA) activity, developed bone lesions that were derived from cAMP-responsive osteogenic cells and resembled fibrous dysplasia (FD). Prkar1a +/− mice were crossed with mice that were heterozygous for catalytic subunit Cα (Prkaca), the main PKA activity-mediating molecule, to generate a mouse model with double heterozygosity for prkar1a and prkaca (Prkar1a). Unexpectedly, Prkar1amice developed a greater number of osseous lesions starting at 3 months of age that varied from the rare chondromas in the long bones and the ubiquitous osteochondrodysplasia of vertebral bodies to the occasional sarcoma in older animals. Cells from these lesions originated from an area proximal to the growth plate, expressed osteogenic cell markers, and showed higher PKA activity that was mostly type II (PKA-II) mediated by an alternate pattern of catalytic subunit expression. Gene expression profiling confirmed a preosteoblastic nature for these cells but also showed a signature that was indicative of mesenchymal-to-epithelial transition and increased Wnt signaling. These studies show that a specific subpopulation of aBSCs can be stimulated in adult bone by alternate PKA and catalytic subunit activity; abnormal proliferation of these cells leads to skeletal lesions that have similarities to human FD and bone tumors.

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Section: Discussionmentioning

confidence: 53%

Alternate protein kinase A activity identifies a unique population of stromal cells in adult bone

Tsang

Starost

Nesterova

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…For instance, a small molecule could be identified to activate signaling pathways that stimulate osteoblast-associated gene expression and matrix mineralization, which are processes associated with bone formation [199]. In fact, data from our group and others demonstrated that small molecule cyclic adenosine monophosphate (cAMP) analogs were able to induce in vitro and in vivo bone formation through the Protein Kinase A (PKA)/cAMP response element-binding protein (CREB) signaling mechanism [200][201][202][203]. It is also worth noting that the advances in high throughput screening technologies have yielded a large number of other osteoinductive small molecules in the past decade [176].…”

Section: Small Molecule Deliverymentioning

confidence: 99%

Electrospinning of polymer nanofibers for tissue regeneration

Jiang

Carbone

et al. 2015

Progress in Polymer Science

437

242

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Repair and regeneration of human tissues and organs using biomaterials, cells, and/or growth factors is a great challenge for tissue engineers and surgeons. The convergence of advanced materials science, nanotechnology, stem cell science, and developmental biology, which we define as Regenerative Engineering, represents the next multidisciplinary paradigm to engineer complex tissues. One of the grand challenges in this field is to mimic closely the hierarchical architecture and properties of the extracellular matrices (ECM) of the native tissues.A bio-inspired approach to creating biomaterials with nanoscale topographical features, microand macroscale gradient structures, and biological domains to interact with target growth factors and cells is key to overcoming this challenge for successful tissue regeneration. Furthermore, the healing and repair of diseased musculoskeletal tissues rely on many signaling pathways, involving numerous growth factors and their receptors. Thus, pharmacological manipulation of the signaling pathways with bioactive molecules is an important component of tissue regeneration. This review summarizes current strategies to develop advanced nanofibrous polymer-based scaffolds via electrospinning, their applications in regenerating human musculoskeletal tissues, and the use of polymer nanofibers to deliver growth factors or small molecules for regenerative medicine.

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“…It has been shown that vascular smooth muscle cells and skeletal osteoblasts respond oppositely to the same stimuli, such as oxidized phospholipids and continuous activation of the PKA pathway (as in hyperparathyroidism) (3,24,(33)(34)(35)(36)(37), i.e. these factors promote osteoblastic differentiation of vascular cells but inhibit osteoblastic differentiation of bone cells.…”

Section: Table 2 Effect Of Pki On Tnf-␣ Induction Of Ranklmentioning

confidence: 99%

PKA-induced Receptor Activator of NF-κB Ligand (RANKL) Expression in Vascular Cells Mediates Osteoclastogenesis but Not Matrix Calcification

Tseng

Graham

Geng

et al. 2010

Journal of Biological Chemistry

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Vascular calcification is a predictor of cardiovascular mortality and is prevalent in patients with atherosclerosis and chronic renal disease. It resembles skeletal osteogenesis, and many bone cells as well as bone-related factors involved in both formation and resorption have been localized in calcified arteries. Previously, we showed that aortic medial cells undergo osteoblastic differentiation and matrix calcification both spontaneously and in response to PKA agonists. The PKA signaling pathway is also involved in regulating bone resorption in skeletal tissue by stimulating osteoblast-production of osteoclast regulating cytokines, including receptoractivator of nuclear B ligand (RANKL) and interleukins. Therefore, we investigated whether PKA activators regulate osteoclastogenesis in aortic smooth muscle cells (SMC). Treatment of murine SMC with the PKA agonist forskolin stimulated RANKL expression at both mRNA and protein levels. Forskolin also stimulated expression of interleukin-6 but not osteoprotegerin (OPG), an inhibitor of RANKL. Consistent with these results, osteoclastic differentiation was induced when monocytic preosteoclasts (RAW264.7) were cocultured with forskolin-treated aortic SMC. Oxidized phospholipids also slightly induced RANKL expression in T lymphocytes, another potential source of RANKL in the vasculature. Because previous studies have shown that RANKL treatment alone induces matrix calcification of valvular and vascular cells, we next examined whether RANKL mediates forskolin-induced matrix calcification by aortic SMC. RANKL inhibition with OPG had little or no effect on osteoblastic differentiation and matrix calcification of aortic SMC. These findings suggest that, as in skeletal tissues, PKA activation induces bone resorptive factors in the vasculature and that aortic SMC calcification specifically induced by PKA, is not mediated by RANKL.

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cAMP/PKA Signaling Inhibits Osteogenic Differentiation and Bone Formation in Rodent Models

Cited by 44 publications

References 58 publications

Alternate protein kinase A activity identifies a unique population of stromal cells in adult bone

Alternate protein kinase A activity identifies a unique population of stromal cells in adult bone

Electrospinning of polymer nanofibers for tissue regeneration

PKA-induced Receptor Activator of NF-κB Ligand (RANKL) Expression in Vascular Cells Mediates Osteoclastogenesis but Not Matrix Calcification

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