Metabolic Acidosis Stimulates RANKL RNA Expression in Bone Through a Cyclo-oxygenase-Dependent Mechanism

Frick, Kevin K.; Bushinsky, David A.

doi:10.1359/jbmr.2003.18.7.1317

Cited by 92 publications

(89 citation statements)

References 72 publications

(237 reference statements)

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“…Metabolic acidosis, another factor that is capable of stimulating osteoblast activity by upregulating PTH/PTHrP receptors (39) and increasing the expression of RANKL (40), was not present in our patients as judged by the normal serum CO 2 concentrations.…”

Section: Discussionmentioning

confidence: 57%

Increased Osteoblastic Activity and Expression of Receptor Activator of NF-κB Ligand in Nonuremic Nephrotic Syndrome

Freundlich¹,

Alonzo²,

Bellorín-Font³

et al. 2005

Journal of the American Society of Nephrology

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Patients with nephrotic syndrome (NS), even with normal GFR, often display altered mineral homeostasis and abnormal bone histology. However, the latter, mostly osteomalacia and increased bone resorption, cannot be readily explained by the prevalent concentrations of parathyroid hormone and vitamin D metabolites. The transmembrane receptor activator of NF-B ligand (RANKL) of osteoblasts is essential for osteoclast formation and differentiation. Osteoblasts activity and the expression of RANKL were tested in cultures of normal human osteoblasts with sera obtained from patients with NS and normal GFR (129 ؎ 26 ml/min per 1.73 m 2 ) during relapse and remission of their NS. Osteoblasts that were cultured in vitro with sera during relapse displayed elevated concentrations of alkaline phosphatase (AP) and increased expression of RANKL. By contrast, during remission, AP concentrations were significantly lower (P < 0.05) and RANKL expression notably attenuated or absent. AP correlated with the proteinuria (r ‫؍‬ 0.5, P < 0.05) and was not significantly affected by the therapeutic administration of corticosteroids. Whereas parathyroid hormone levels were normal (35 ؎ 21 pg/ml), the serum markers of bone formation (osteocalcin and bone-specific alkaline phosphatase) were lower during relapse compared with remission. Thus, sera from patients with NS and normal GFR stimulate the activity of osteoblasts and upregulate their expression of RANKL. These alterations, more prominent during clinically active NS, are transient and reversible upon remission. These disturbances of bone biology may play an important pathogenic role in the abnormal bone histology observed in patients with NS even before a decline in GFR occurs.

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Section: Discussionmentioning

confidence: 57%

Increased Osteoblastic Activity and Expression of Receptor Activator of NF-κB Ligand in Nonuremic Nephrotic Syndrome

Freundlich¹,

Alonzo²,

Bellorín-Font³

et al. 2005

Journal of the American Society of Nephrology

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“…(Direct effects of low pH on osteoblasts in vitro have previously been reported (28,29,30). Acidification down to pH 7.0 decrease proliferation, collagen synthesis, and ALP activity in comparison with pH 7.4 (28,29).…”

Section: Discussionmentioning

confidence: 87%

Variation of pH in lysed platelet concentrates influence proliferation and alkaline phosphatase activity in human osteoblast-like cells

et al. 2007

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Interestingly, we also found BMP-2 in platelet lysate. However BMP-2 was only present in LPB pH 4.0. We suggest, based on these experimental findings, that acidic milieu influence platelets to release growth factors more potent to stimulate osteoblast proliferation than neutral and alkaline platelet preparations. Lysed platelet concentrates prepared at an alkaline pH might release additional components with stimulating effects pH of platelet concentrate and growth stimulation 4 resulting in other features than cell proliferation. This is the first report, to our knowledge, about the presence of BMP-2 in platelet lysate and about a pH dependent stimulatory effect of lysed platelet concentrates on human osteoblast-like cell proliferation. Lysed platelet concentrates, preincubated in acidic or alkaline buffers, may benefit fracture healing, implant fixation and might also be advantageous in the treatment of wounds with platelet constituents; however, this has to be investigated in extended experimental and clinical settings.pH of platelet concentrate and growth stimulation 5

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“…Similarly, increased HCO 3 Ϫ that results from reduced acid production is not secreted but is balanced by K ϩ and Ca 2ϩ . Recent work by Bushinsky and co-workers (16,17) showed that metabolic acidosis suppresses bone formation by osteoblasts and, via a cyclo-oxygenase-dependent mechanism, increases RANKL synthesis, thereby increasing osteoclast differentiation and bone resorption. Work by Ludwig et al (7) showing that protons bind OGR1 via extracellular histidines and that OGR1 was localized in osteoblasts and osteocytes led them to speculate that the effects of pH on the bone-forming side were mediated by OGR1.…”

Section: Discussionmentioning

confidence: 99%

Expression of and Role for Ovarian Cancer G-protein-coupled Receptor 1 (OGR1) during Osteoclastogenesis

Yang

Mailhot

Birnbaum

et al. 2006

Journal of Biological Chemistry

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Osteoclasts differentiate from hematopoietic mononuclear precursor cells under the control of both colony stimulating factor-1 (CSF-1, or M-CSF) and receptor activator of NF-B ligand (RANKL, or TRANCE, TNFSF11) to carry out bone resorption. Using high density gene microarrays, we followed gene expression changes in long bone RNA when CSF-1 injections were used to restore osteoclast populations in the CSF-1-null toothless (csf1 tl /csf1 tl ) osteopetrotic rat. We found that ovarian cancer G-protein-coupled receptor 1 (OGR1, or GPR68) was strongly up-regulated, rising >6-fold in vivo after 2 days of CSF-1 treatments. OGR1 is a dual membrane receptor for both protons (extracellular pH) and lysolipids. Strong induction of OGR1 mRNA was also observed by microarray, real-time RT-PCR, and immunoblotting when mouse bone marrow mononuclear cells and RAW 264.7 pre-osteoclast-like cells were treated with RANKL to induce osteoclast differentiation. Anti-OGR1 immunofluorescence showed intense labeling of RANKL-treated RAW cells. The time course of OGR1 mRNA expression suggests that OGR1 induction is early but not immediate, peaking 2 days after inducing osteoclast differentiation both in vivo and in vitro. Specific inhibition of OGR1 by anti-OGR1 antibody and by small inhibitory RNA inhibited RANKL-induced differentiation of both mouse bone marrow mononuclear cells and RAW cells in vitro, as evidenced by a decrease in tartrate-resistant acid phosphatase-positive osteoclasts. Taken together, these data indicate that OGR1 is expressed early during osteoclastogenesis both in vivo and in vitro and plays a role in osteoclast differentiation.The catabolic removal of bone during skeletal formation and remodeling requires the specialized activity of multinucleated osteoclasts. Osteoclasts differentiate by fusion of hematopoietic mononuclear precursors in response to systemic and local signals, in particular colony-stimulating factor-1 (CSF-1, 2 or M-CSF) and the tumor necrosis factor family member receptor activator of NF-B ligand (RANKL, or TRANCE, TNFSF11) (1). Excessive osteoclast activity systemically leads to osteopenias such as osteoporosis, whereas local hyperactivity can lead to osteolysis as seen in tumor metastases to bone or in prosthesis loosening. Hypoactivity of osteoclasts can lead to sclerosing bone disorders, for example in genetic conditions such as osteopetrosis.Osteoclast differentiation is a complex process that requires the coordinated action of many gene products, including not only extrinsic factors such as CSF-1 and RANKL, which are supplied by osteoblasts locally in bone tissue, but also intrinsic factors required for osteoclast function. Mononuclear precursors must migrate to sites where resorption is needed, fuse to form multinucleated pre-osteoclasts, and attach firmly to bone. They develop highly specialized cellular structures, including an actin ring that forms a tight seal with the bone surface, and a highly convoluted plasma membrane domain called the ruffled border, which is the site of extremely a...

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Metabolic Acidosis Stimulates RANKL RNA Expression in Bone Through a Cyclo-oxygenase-Dependent Mechanism

Cited by 92 publications

References 72 publications

Increased Osteoblastic Activity and Expression of Receptor Activator of NF-κB Ligand in Nonuremic Nephrotic Syndrome

Increased Osteoblastic Activity and Expression of Receptor Activator of NF-κB Ligand in Nonuremic Nephrotic Syndrome

Variation of pH in lysed platelet concentrates influence proliferation and alkaline phosphatase activity in human osteoblast-like cells

Expression of and Role for Ovarian Cancer G-protein-coupled Receptor 1 (OGR1) during Osteoclastogenesis

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