Protein phosphatases: Possible bisphosphonate binding sites mediating stimulation of osteoblast proliferation

Morelli, Susana; Bilbao, P.; Katz, S; Lezcano, Virginia; Roldán, Emilio; Boland, Ricardo; Santillán, Graciela

doi:10.1016/j.abb.2010.12.013

Cited by 30 publications

(36 citation statements)

References 31 publications

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“…Under BP treatment inhibition of bone resorption is coupled with a lower bone formation. Nevertheless, in most treated patients bone mass and strength were increased and fracture incidence was reduced, especially in osteoporotic women, suggesting a balance 'anabolic' effect 16,17 . In patients with high baseline values of bone turnover markers, an average 40-60% reduction is usually observed after BP treatment.…”

Section: Introductionmentioning

confidence: 99%

“…In patients with high baseline values of bone turnover markers, an average 40-60% reduction is usually observed after BP treatment. In patients who are unable or not willing to do regular exercise, a combination of ALN and WBV treatments may improve the anabolic outcome 16,17 . Results might be optimized by avoiding any negative interaction between drug and physical impacts at the bone cellular level (i.e.…”

Section: Introductionmentioning

confidence: 99%

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A controlled trial comparing one-year biochemical bone metabolism outcome in postmenopausal frail osteopenic women under weekly alendronate treatment, with or without whole-body vibration intervention

Capiglioni¹,

Acotto²,

Marino³

et al. 2016

JFSF

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A controlled trial comparing one-year biochemical bone metabolism outcome in postmenopausal frail osteopenic women under weekly alendronate treatment, with or without whole-body vibration intervention

Capiglioni¹,

Acotto²,

Marino³

et al. 2016

JFSF

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“…We have previously reported that [ 3 H]-olpadronate uptake is a fast event, as 56% of total binding was taken up within 5 min. In addition, we observed specific [ 3 H]-olpadronate binding to different subcellular fractions obtained from osteoblastic cells [10] indicating non selective intracellular localization of the drug. To further study the osteoblastic BP uptake we synthesized ALN labeled fluorescently with Alexa Fluor 488 (AF-ALN) following the method described by Thompson et al [6].…”

Section: Alendronate Is Internalized By Cells and Cx43 Is Not The Roumentioning

confidence: 83%

“…In this regard, we have recently reported that olpadronate specifically binds to osteoblastic cells [10]. The requirement of Cx43 for antiapoptosis by BPs has raised the possibility that interaction of BPs with Cx43 present in the cell membrane results in hemichannel opening, thereby initiating intracellular survival signaling.…”

Section: Introductionmentioning

confidence: 99%

“…We did not observe responses employing either a lower concentration of ALN (1 M) or a shorter incubation time of cells with the BP (24 h). According to previous studies of our laboratory [10], we employed phosphatase inhibitors as positive controls of cellular proliferation. Both, NaF and Na 3 VO 4 , stimulated [ 3 H]-thymidine incorporation at 24 and 48 h of treatment.…”

Section: Aln Induces Osteoblasts Proliferation Independently Of Cx43 mentioning

confidence: 99%

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Role of connexin 43 in the mechanism of action of alendronate: Dissociation of anti-apoptotic and proliferative signaling pathways

Lezcano

Boland

Morelli

2011

Bone

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Bisphosphonates (BPs) inhibit osteocyte and osteoblast apoptosis via opening of connexin (Cx) 43 hemichannels and activating the extracellular signal regulated kinases ERKs. Previously, we hypothesized that intracellular survival signaling is initiated by interaction of BPs with Cx43. However, using whole cell binding assays with [ 3 H]-alendronate, herein we demonstrated the presence of saturable, specific and high affinity binding sites in the Cx43-expressing ROS 17/2.8 osteoblastic cells, authentic osteoblasts and MLO-Y4 cells expressing Cx43 or not, as well as in HeLa cells lacking Cx43 expression and ROS 17/2.8 cells pretreated with agents that disassemble Cx channels. In addition, both BPs and the PTP inhibitor Na 3 VO 4 increased proliferation of cells expressing Cx43 or not. Furthermore, although BPs are internalized and inhibit intracellular enzymes in osteoclasts, whether the drugs penetrate non-resorptive bone cells is not known. To clarify this, we evaluated the osteoblastic uptake of AF-ALN, a fluorescently labeled analog of alendronate. AF-ALN was rapidly internalized in cells expressing Cx43 or not indicating that this process is not mediated via Cx43 hemichannels. Altogether, these findings suggest that although required for triggering intracellular survival signaling by BPs, Cx43 is dispensable for cellular BP binding, its uptake, as well as the proliferative effects of these agents.

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Connexin 43 and ERK regulate tension-induced signal transduction in human periodontal ligament fibroblasts

Zhang

et al. 2015

J. Orthop. Res.

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Periodontal ligament (PDL) fibroblasts play an important role in preserving periodontal homeostasis and transmitting mechanical signals to alveolar bone. Connexin 43 (Cx43), a gap junction protein, is essential for bone homeostasis and regulates bone remodeling. However, the function of Cx43 in human PDL fibroblast-regulated bone remodeling has not yet been elucidated. In this study, human PDL fibroblasts were exposed to cyclic mechanical tension with a maximum 5% elongation for different durations. We then examined the expression of signaling molecules related to osteogenesis and osteoclastogenesis at both the mRNA and protein levels as well as the activity of extracellular signal-regulated kinase (ERK) in human PDL fibroblasts after loading. We found that mechanical tension increased Cx43, which further upregulated osteogenic (e.g., RUNX2, Osterix, and OPG) and down-regulated osteoclastogenic (e.g., RANKL) signaling molecules. Suppressing Cx43 gene (Gja1) by siRNA inhibited the increase in osteogenesisrelated molecules but enhanced RANKL expression. Similar to Cx43, activated ERK1/2 was also enhanced by mechanical tension and suppressed by Cx43 siRNA. Inhibition of ERK1/2 signaling using PD98059 reduced the tension-regulated increase in osteogenesisrelated molecules but enhanced that of osteoclastogenesis-related ones. These findings suggest that cyclic tension may involve into the osteogenic or osteoclastogenetic differentiation potential of human PDL fibroblasts via the Cx43-ERK1/2 signaling pathway. ß

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Protein phosphatases: Possible bisphosphonate binding sites mediating stimulation of osteoblast proliferation

Cited by 30 publications

References 31 publications

A controlled trial comparing one-year biochemical bone metabolism outcome in postmenopausal frail osteopenic women under weekly alendronate treatment, with or without whole-body vibration intervention

A controlled trial comparing one-year biochemical bone metabolism outcome in postmenopausal frail osteopenic women under weekly alendronate treatment, with or without whole-body vibration intervention

Role of connexin 43 in the mechanism of action of alendronate: Dissociation of anti-apoptotic and proliferative signaling pathways

Connexin 43 and ERK regulate tension-induced signal transduction in human periodontal ligament fibroblasts

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