Tartronates: A New Generation of Drugs Affecting Bone Metabolism

Caselli, Gianfranco; Mantovanini, Marco; Gandolfi, C.; Allegretti, Marcello; Fiorentino, Simonetta; Pellegrini, Luigi; Melillo, G.; Bertini, Riccardo; Sabbatini, Wilma; Anacardio, Roberto; Clavenna, G.; Sciortino, Giancarlo; Teti, Anna

doi:10.1359/jbmr.1997.12.6.972

Cited by 45 publications

(39 citation statements)

References 37 publications

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“…The numbers of pits per each category were scored by multiplying by a different factor according to their dimensions: for small pits, 0.3; for medium pits, 1; and for large pits, 3. The sum of the three scores gave the pit index 28 .…”

Section: Methodsmentioning

confidence: 99%

c-Src and IL-6 inhibit osteoblast differentiation and integrate IGFBP5 signalling

et al. 2012

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Interleukin-6 (IL-6) and c-src impair osteoblast maturation in vitro and in vivo. Given the similar effects of these factors, they are likely to establish a functional loop to maintain osteoblasts in a less mature status. Here we describe a pathway whereby c-src stimulates IL-6 expression through the sTAT3 factor, which, in response to IL-6 induces insulin-like growth factor 5 (IGFBP5), a c-src activating factor that amplifies this loop only in immature osteoblasts. In contrast, in mature osteoblasts, IGFBP5 is enhanced by Runx2, but is no longer able to stimulate c-src activation, as this tyrosine kinase at this stage is downregulated. We find that the IGFBP5 produced by osteoblasts stimulates osteoclastogenesis and bone resorption, acting as an osteoblast-osteoclast coupling factor. Finally, we demonstrate that the integrated actions of c-src, IL-6 and IGFBP5 also have a role in vivo. We conclude that this pathway is relevant for bone metabolism, both in physiological and in pathological conditions.

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Section: Methodsmentioning

confidence: 99%

c-Src and IL-6 inhibit osteoblast differentiation and integrate IGFBP5 signalling

et al. 2012

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“…Cells were then removed by ultrasonication in 1% sodium hypochlorite, and slices were stained with 0.1% toluidine blue. Pits were counted and the pit index computed according to Caselli et al (Caselli et al, 1997).…”

Section: Osteoclast Primary Culturesmentioning

confidence: 99%

Osteopenia, decreased bone formation and impaired osteoblast development inSox4heterozygous mice

Nissen‐Meyer

Jemtland

Gautvik

et al. 2007

Journal of Cell Science

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The transcription factor Sox4 is vital for fetal development, as Sox4–/– homozygotes die in utero. Sox4 mRNA is expressed in the early embryonic growth plate and is regulated by parathyroid hormone, but its function in bone modeling/remodeling is unknown. We report that Sox4+/– mice exhibit significantly lower bone mass (by dual-energy X-ray absorptiometry) from an early age, and fail to obtain the peak bone mass of wild-type (WT) animals. Microcomputed tomography (μCT), histomorphometry and biomechanical testing of Sox4+/– bones show reduced trabecular and cortical thickness, growth plate width, ultimate force and stiffness compared with WT. Bone formation rate (BFR) in 3-month-old Sox4+/– mice is 64% lower than in WT. Primary calvarial osteoblasts from Sox4+/– mice demonstrate markedly inhibited proliferation, differentiation and mineralization. In these cultures, osterix (Osx) and osteocalcin (OCN) mRNA expression was reduced, whereas Runx2 mRNA was unaffected. No functional defects were found in osteoclasts. Silencing of Sox4 by siRNA in WT osteoblasts replicated the defects observed in Sox4+/– cells. We demonstrate inhibited formation and altered microarchitecture of bone in Sox4+/– mice versus WT, without apparent defects in bone resorption. Our results implicate the transcription factor Sox4 in regulation of bone formation, by acting upstream of Osx and independent of Runx2.

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“…Bone slices were then fixed in 3% paraformaldehyde in 0.1 M cacodylate buffer, cells were removed by ultrasonication in 1% sodium hypochlorite, and slices were stained with 0.1% Toluidine Blue. Pits were counted and the pit index computed according to the method of Caselli et al (Caselli et al, 1997).…”

Section: Bone Resorptionmentioning

confidence: 99%

A novel protein kinase C α-dependent signal to ERK1/2 activated by αVβ3 integrin in osteoclasts and in Chinese hamster ovary (CHO) cells

Rucci

DiGiacinto

Orrù

et al. 2005

Journal of Cell Science

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We identified a novel protein kinase C (PKC)α-dependent signal to extracellular signal-regulated kinase (ERK)1/2 in mouse osteoclasts and Chinese hamster ovary (CHO) cells, specifically activated by the αVβ3 integrin. It involves translocation (i.e. activation) of PKCα from the cytosol to the membrane and/or the Triton X-100-insoluble subcellular fractions, with recruitment into a complex with αVβ3 integrin, growth factor receptor-bound protein (Grb2), focal adhesion kinase (FAK) in CHO cells and proline-rich tyrosine kinase (PYK2) in osteoclasts. Engagement of αvβ3 integrin triggered ERK1/2 phosphorylation, but the underlying molecular mechanism was surprisingly independent of the well known Shc/Ras/Raf-1 cascade, and of phosphorylated MAP/ERK kinase (MEK)1/2, so far the only recognized direct activator of ERK1/2. In contrast, PKCα was involved in ERK1/2 activation because inhibition of its activity prevented ERK1/2 phosphorylation. The tyrosine kinase c-Src also contributed to ERK1/2 activation, however, it did not interact with PKCα in the same molecular complex. The αVβ3/PKCα complex formation was fully dependent upon the intracellular calcium concentration ([Ca2+]i), and the use of the intracellular Ca2+ chelator 1,2-bis(o-amino-phenoxy)ethane-N,N,N′,N′-tetraaceticacidtetra (acetoxymethyl) ester (BAPTA-AM) also inhibited PKCα translocation and ERK1/2 phosphorylation. Functional studies showed that αVβ3 integrin-activated PKCα was involved in cell migration and osteoclast bone resorption, but had no effect on the ability of cells to attach to LM609, suggesting a role in events downstream of αVβ3 integrin engagement.

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Tartronates: A New Generation of Drugs Affecting Bone Metabolism

Cited by 45 publications

References 37 publications

c-Src and IL-6 inhibit osteoblast differentiation and integrate IGFBP5 signalling

c-Src and IL-6 inhibit osteoblast differentiation and integrate IGFBP5 signalling

Osteopenia, decreased bone formation and impaired osteoblast development inSox4heterozygous mice

A novel protein kinase C α-dependent signal to ERK1/2 activated by αVβ3 integrin in osteoclasts and in Chinese hamster ovary (CHO) cells

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