ERK1/2-activated de Novo Mapkapk2 Synthesis Is Essential for Osteogenic Growth Peptide Mitogenic Signaling in Osteoblastic Cells

Miguel, Symone M. San; Namdar-Attar, M; Noh, Tommy; Frenkel, Baruch; Bab, Itai

doi:10.1074/jbc.m503861200

Cited by 43 publications

(45 citation statements)

References 52 publications

(54 reference statements)

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“…We have previously reported in these cells that prolonged Gi-protein activation of Erk1/2, beyond 30 min leads to transcriptional activation of Mapkapk2 and Cyclic AMP-responsive element binding (CREB) phosphorylation (16). However, OS failed to increase Mapkapk2 expression (Fig.…”

Section: Discussionmentioning

confidence: 89%

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Oleoyl serine, an endogenous N -acyl amide, modulates bone remodeling and mass

Smoum

Bar²,

Tan

et al. 2010

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

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Bone mass is determined by a continuous remodeling process, whereby the mineralized matrix is being removed by osteoclasts and subsequently replaced with newly formed bone tissue produced by osteoblasts. Here we report the presence of endogenous amides of long-chain fatty acids with amino acids or with ethanolamine (N-acyl amides) in mouse bone. Of these compounds, N-oleoyl-L-serine (OS) had the highest activity in an osteoblast proliferation assay. In these cells, OS triggers a Gi-protein-coupled receptor and Erk1/2. It also mitigates osteoclast number by promoting osteoclast apoptosis through the inhibition of Erk1/2 phosphorylation and receptor activator of nuclear-κB ligand (RANKL) expression in bone marrow stromal cells and osteoblasts. In intact mice, OS moderately increases bone volume density mainly by inhibiting bone resorption. However, in a mouse ovariectomy (OVX) model for osteoporosis, OS effectively rescues bone loss by increasing bone formation and markedly restraining bone resorption. The differential effect of exogenous OS in the OVX vs. intact animals is apparently a result of an OVX-induced decrease in skeletal OS levels. These data show that OS is a previously unexplored lipid regulator of bone remodeling. It represents a lead to antiosteoporotic drug discovery, advantageous to currently available therapies, which are essentially either proformative or antiresorptive.fatty acyl amides I n mammals, including humans, bone mass is determined by an unremitting remodeling process whereby the mineralized matrix is continuously removed by osteoclasts and subsequently replaced with newly formed bone tissue produced by osteoblasts. This process is regulated by autocrine/paracrine factors, such as receptor activator of nuclear-κB ligand (RANKL), osteoprotegerin (OPG), bone morphogenetic proteins, and Wnt, as well as circulating hormones (e.g., sex steroids, parathyroid hormone) and brain-derived signals (e.g., sympathetic, pituitary) (1-3). Imbalanced bone remodeling leads to skeletal pathologies, mainly osteoporosis, the most common degenerative disorder in affluent societies, which results from a net increase in bone resorption (4). Identification of endogenous constituents, which regulate bone remodeling and skeletal mass, contributes to the elucidation of the mechanisms involved in this process and offers promise for developing novel antiosteoporotic pharmacotherapy.Amides of long-chain fatty acids with amino acids or with ethanolamine (N-acyl amides) represent a major group of endogenous lipids. In mammalian tissues they have numerous physiological functions. For example, anandamide (arachidonoyl ethanolamide) is the first identified endogenous psychoactive ligand of cannabinoid receptors (5); arachidonoyl serine is an endogenous vasodilator, which does not bind to the cannabinoid receptors (6); and oleoyl ethanolamide is an endogenous structural analog to anandamide that regulates food intake through the activation of GPR 119 (7, 8). The well-established biosynthetic tendency to follow existing p...

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Section: Discussionmentioning

confidence: 89%

“…In an osteoblast proliferation screening assay (16), OS and the related compounds presented in Fig. 1A stimulated cell number dose-dependently.…”

Section: Os Occurs Naturally In Bonementioning

confidence: 99%

Oleoyl serine, an endogenous N -acyl amide, modulates bone remodeling and mass

Smoum

Bar²,

Tan

et al. 2010

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

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“…On the other hand, knockdown of ELK-1 partially abolished the increase in BMP-2 mRNA levels, suggesting that other transcription factors in addition to Elk-1 are involved in the increase. Because the nuclear transcription factors cAMP-response element-binding protein and STAT-3, which are located downstream of ERK1/2 (45, 46), activate osteoblast differentiation (47)(48)(49), cAMP-response elementbinding protein or STAT3 as well as Elk-1 may be the transcription factors involved in the enhancement of BMP-2 mRNA expression in HCEM cells stimulated by BDNF.…”

Section: Discussionmentioning

confidence: 99%

Brain-derived Neurotrophic Factor Stimulates Bone/Cementum-related Protein Gene Expression in Cementoblasts

Kajiya¹,

Shiba²,

Fujita³

et al. 2008

Journal of Biological Chemistry

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Brain-derived neurotrophic factor (BDNF), recognized as essential in the developing nervous system, is involved in differentiation and proliferation in non-neuronal cells, such as endothelial cells, osteoblasts, and periodontal ligament cells. We have focused on the application of BDNF to the regeneration of periodontal tissue and indicated that BDNF promotes the regeneration of experimentally created periodontal defects. Cementoblasts form cementum, mineralized tissue, which is key to establishing a functional periodontium. The application of BDNF to the regeneration of periodontal tissue requires elucidation of the mechanism by which BDNF regulates the functions of cementoblasts. In this study, we examined how BDNF regulates the mRNA expression of bone/cementum-related proteins (alkaline phosphatase (ALP), osteopontin (OPN), and bone morphogenetic protein-2 (BMP-2)) in cultures of immortalized human cementoblast-like (HCEM) cells. BDNF elevated the mRNA levels of ALP, OPN, and BMP-2 in HCEM cells. Small interfering RNA (siRNA) for TRKB, a high affinity receptor of BDNF, siRNA for ELK-1, which is a downstream target of ERK1/2, and PD98059, an ERK inhibitor, obviated the increase in the mRNA levels. BDNF increased the levels of phosphorylated ERK1/2 and Elk-1, and the blocking of BDNF signaling by treatment with siRNA for TRKB and PD98059 suppressed the phosphorylation of ERK1/2 and Elk-1. Furthermore, BDNF increased the levels of phosphorylated c-Raf, which activates the ERK signaling pathway. These findings provide the first evidence that the TrkB-c-Raf-ERK1/2-Elk-1 signaling pathway is required for the BDNF-induced mRNA expression of ALP, OPN, and BMP-2 in HCEM cells.

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“…The Position of each gene in the pathway can be assigned by treating cells sequentially with siRNAs targeting the various genes in the pathway and assaying which genes are affected. This technology has been widely used in defining gene function in transforming growth factor beta (TGF-beta) pathway [41], mitogenic signaling pathway in osteoblasts [42], insulin signaling [43] and other human signaling pathways [44].…”

Section: Pathway Analysismentioning

confidence: 99%

RNA Interference and Potential Applications

Zhou¹,

He²,

Wang³

et al. 2006

CTMC

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RNA interference (RNAi) is the process of using specific sequences of double-stranded RNA (dsRNA) to knock down the expression level of sequence-homologous genes. Such ability of small interfering RNA (siRNA) in mammalian cells will undoubtedly revolutionize the study of functional genomics, the discovery of drug targets and even the treatment of human diseases. In this review we briefly describe the history of RNAi discovery, the RNAi mechanism and the general guideline for siRNA design as well as various methods for siRNA production and delivery. We also introduce the potential applications of siRNA, inducible siRNA and siRNA library in speeding up basic biomedical research and in acting as potential therapeutic agents for treatment of numerous human diseases.

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ERK1/2-activated de Novo Mapkapk2 Synthesis Is Essential for Osteogenic Growth Peptide Mitogenic Signaling in Osteoblastic Cells

Cited by 43 publications

References 52 publications

Oleoyl serine, an endogenous N -acyl amide, modulates bone remodeling and mass

Oleoyl serine, an endogenous N -acyl amide, modulates bone remodeling and mass

Brain-derived Neurotrophic Factor Stimulates Bone/Cementum-related Protein Gene Expression in Cementoblasts

RNA Interference and Potential Applications

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