Na+/H+ Exchanger Regulatory Factor 1 (NHERF1) Directly Regulates Osteogenesis

Liu, Li; Alonso, V.; Guo, Lei; Tourkova, Irina L.; Henderson, Sarah; Almarza, Alejandro J.; Friedman, Peter A.; Blair, Harry C.

doi:10.1074/jbc.m112.422766

Cited by 28 publications

(31 citation statements)

References 44 publications

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“…This reflects a decrease in to mature crosslinks in the knock out mice, which might have a serious impact on bone mechanics. A similar~30% reduction of collagen cross-linking was reported by Liu et al 28 for NHERF-1 − / − relative to WT mice. To examine further how changes in collagen crosslinks reflect alterations in bone strength we tested the biomechanical properties of femora by three-point bending.…”

Section: Apoa-1 Deficiency Results In Reduced Bone Masssupporting

confidence: 67%

“…This was unexpected since, in osteoblasts, NHERF-1 regulates mineral accumulation and its absence is another factor that promotes adipogenesis. 28 Because PPAR-γ and RUNX2 are of central importance in adipocyte and osteoblast differentiation, respectively, the PCR results were confirmed by Western blotting and flow cytometric analysis (Figures 5b and c). Additional assays with interesting results but unclear meaning included analysis for ALP and apoA-2 in apoA-1 − / − and WT marrow cells (Supplementary Table S3).…”

Section: Analysis Of Cell Signals Related To Msc Differentiationmentioning

confidence: 59%

“…36 which is required for normal osteoblast function and in its absence adipocyte differentiation increases. 28 Hence, our finding might reflect that NHERF-1 is important in osteoblast terminal differentiation and its absence promotes adipocyte alternate differentiation, whereas when apoA-1 is present and osteoblast differentiation is disfavored, NHERF-1 might increase in partial compensation. Other late osteoblast mineralization genes the sodium/hydrogen exchangers NHE1 and 6, were invariant but markedly reduced in the NHERF-1-deficient animal.…”

Section: Discussionmentioning

confidence: 80%

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Apolipoprotein A-1 regulates osteoblast and lipoblast precursor cells in mice

Blair

Kalyvioti

Papachristou

et al. 2016

Laboratory Investigation

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Imbalances in lipid metabolism affect bone homeostasis, altering bone mass and quality. A link between bone mass and high-density lipoprotein (HDL) has been proposed. Indeed, it has been recently shown that absence of the HDL receptor scavenger receptor class B type I (SR-B1) causes dense bone mediated by increased adrenocorticotropic hormone (ACTH). In the present study we aimed at further expanding the current knowledge as regards the fascinating bone-HDL connection studying bone turnover in apoA-1-deficient mice. Interestingly, we found that bone mass was greatly reduced in the apoA-1-deficient mice compared with their wild-type counterparts. More specifically, static and dynamic histomorphometry showed that the reduced bone mass in apoA-1 − / − mice reflect decreased bone formation. Biochemical composition and biomechanical properties of ApoA-1 − / − femora were significantly impaired. Mesenchymal stem cell (MSC) differentiation from the apoA-1 − / − mice showed reduced osteoblasts, and increased adipocytes, relative to wild type, in identical differentiation conditions. This suggests a shift in MSC subtypes toward adipocyte precursors, a result that is in line with our finding of increased bone marrow adiposity in apoA-1 − / − mouse femora. Notably, osteoclast differentiation in vitro and osteoclast surface in vivo were unaffected in the knock-out mice. In whole bone marrow, PPARγ was greatly increased, consistent with increased adipocytes and committed precursors. Further, in the apoA-1 − / − mice marrow, CXCL12 and ANXA2 levels were significantly decreased, whereas CXCR4 were increased, consistent with reduced signaling in a pathway that supports MSC homing and osteoblast generation. In keeping, in the apoA-1 − / − animals the osteoblast-related factors Runx2, osterix, and Col1a1 were also decreased. The apoA-1 − / − phenotype also included augmented CEPBa levels, suggesting complex changes in growth and differentiation that deserve further investigation. We conclude that the apoA-1 deficiency generates changes in the bone cell precursor population that increase adipoblast, and decrease osteoblast production resulting in reduced bone mass and impaired bone quality in mice.Laboratory Investigation (2016) 96, 763-772; doi:10.1038/labinvest.2016 published online 18 April 2016 Osteoporosis is characterized by low bone mass and microarchitectural deterioration of bone, resulting in bone fragility and fracture susceptibility. 1,2 It is a major public health problem worldwide; indeed, in the United States, more than 44 million people have osteoporosis or low bone mass. 3 The pathogenesis of osteoporosis is multifactorial. Age, sex, body size, metabolic factors, and genetic susceptibility are contributory factors. Interestingly, several studies have shown that there are strong links between bone, fat metabolism, and systemic energy metabolism, and that perturbations in lipid regulatory pathways may trigger both local and systemic phenomena that ultimately affect osteoblast and/or osteoclast function, resulting...

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Section: Apoa-1 Deficiency Results In Reduced Bone Masssupporting

confidence: 67%

Section: Analysis Of Cell Signals Related To Msc Differentiationmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 80%

See 1 more Smart Citation

Apolipoprotein A-1 regulates osteoblast and lipoblast precursor cells in mice

Blair

Kalyvioti

Papachristou

et al. 2016

Laboratory Investigation

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“…NHERF1-null mice display a similar rachitic phenotype but unlike Npt2a knockout animals, the bone phenotype does not spontaneously resolve, suggesting NHERF1 regulates other functions to defend skeletal integrity. Dietary phosphate supplementation of NHERF1-null mice restores serum phosphate levels but the skeletal defects persist [67]. The precise basis for these different actions is unclear but may have to do with the greater urinary phosphate wasting and attendant hypophosphatemia.…”

Section: Discussionmentioning

confidence: 99%

NHERF1 regulation of PTH-dependent bimodal Pi transport in osteoblasts

Wang

Yang

Liu

et al. 2013

Bone

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Control of systemic inorganic phosphate (Pi) levels is crucial for osteoid mineralization. Parathyroid hormone (PTH) mediates actions on phosphate homeostasis mostly by regulating the activity of the type 2 sodium-phosphate cotransporter (Npt2), and this action requires the PDZ protein NHERF1. Osteoblasts express Npt2 and in response to PTH enhance osteogenesis by increasing mineralized matrix. The regulation of Pi transport in osteoblasts is poorly understood. To address this gap we characterized PTH-dependent Pi transport and the role of NHERF1 in primary mouse calvarial osteoblasts. Under proliferating conditions osteoblasts express Npt2a, Npt2b, PTH receptor, and NHERF1. Npt2a mRNA expression was lower in calvarial osteoblasts from NHERF1-null mice. Under basal conditions Pi uptake in osteoblasts from wild-type mice was greater than that of knockout mice. PTH inhibited Pi uptake in proliferating osteoblasts from wild-type mice, but not in cells from knockout mice. In vitro induction of mineralization enhanced osteoblast differentiation and increased osterix and osteocalcin expression. Contrary to the results with proliferating osteoblasts, PTH increased Pi uptake and ATP secretion in differentiated osteoblasts from wild-type mice. PTH had no effect on Pi uptake or ATP release in differentiated osteoblasts from knockout mice. NHERF1 regulation of PTH-sensitive Pi uptake in proliferating osteoblasts is mediated by cAMP/PKA and PLC/PKC, while modulation of Pi uptake in differentiated osteoblasts depends only on cAMP/PKA signaling. The results suggest that NHERF1 cooperates with PTH in differentiated osteoblasts to increase matrix mineralization. We conclude that NHERF1 regulates PTH differentially affects Na-dependent Pi transport at distinct stages of osteoblast proliferation and maturation.

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“…This makes the surface of the osteon a powerful organelle for secreting acid into the extracellular fluid (Liu et al. ). Complementing acid removal, NHERF1 enhances the local activity of the neutral phosphate transporter‐2 (Npt2) providing the essential component phosphate to the osteoblast (Wang et al.…”

Section: Introductionmentioning

confidence: 99%

Chloride-hydrogen antiporters ClC-3 and ClC-5 drive osteoblast mineralization and regulate fine-structure bone patterning in vitro

et al. 2015

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Osteoblasts form an epithelium-like layer with tight junctions separating bone matrix from extracellular fluid. During mineral deposition, calcium and phosphate precipitation in hydroxyapatite liberates 0.8 mole of H+ per mole Ca+2. Thus, acid export is needed for mineral formation. We examined ion transport supporting osteoblast vectorial mineral deposition. Previously we established that Na/H exchangers 1 and 6 are highly expressed at secretory osteoblast basolateral surfaces and neutralize massive acid loads. The Na/H exchanger regulatory factor-1 (NHERF1), a pdz-organizing protein, occurs at mineralizing osteoblast basolateral surfaces. We hypothesized that high-capacity proton transport from matrix into osteoblast cytosol must exist to support acid transcytosis for mineral deposition. Gene screening in mineralizing osteoblasts showed dramatic expression of chloride–proton antiporters ClC-3 and ClC-5. Antibody localization showed that ClC-3 and ClC-5 occur at the apical secretory surface facing the bone matrix and in membranes of buried osteocytes. Surprisingly, the Clcn3−/− mouse has only mildly disordered mineralization. However, Clcn3−/− osteoblasts have large compensatory increases in ClC-5 expression. Clcn3−/− osteoblasts mineralize in vitro in a striking and novel trabecular pattern; wild-type osteoblasts form bone nodules. In mesenchymal stem cells from Clcn3−/− mice, lentiviral ClC-5 shRNA created Clcn3−/−, ClC-5 knockdown cells, validated by western blot and PCR. Osteoblasts from these cells produced no mineral under conditions where wild-type or Clcn3−/− cells mineralize well. We conclude that regulated acid export, mediated by chloride–proton exchange, is essential to drive normal bone mineralization, and that CLC transporters also regulate fine patterning of bone.

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Na+/H+ Exchanger Regulatory Factor 1 (NHERF1) Directly Regulates Osteogenesis

Cited by 28 publications

References 44 publications

Apolipoprotein A-1 regulates osteoblast and lipoblast precursor cells in mice

Apolipoprotein A-1 regulates osteoblast and lipoblast precursor cells in mice

NHERF1 regulation of PTH-dependent bimodal Pi transport in osteoblasts

Chloride-hydrogen antiporters ClC-3 and ClC-5 drive osteoblast mineralization and regulate fine-structure bone patterning in vitro

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