How To Build a Bone: PHOSPHO1, Biomineralization, and Beyond

Dillon, Scott; Staines, Katherine; Millán, José Luis; Farquharson, Colin

doi:10.1002/jbm4.10202

Cited by 50 publications

(51 citation statements)

References 156 publications

(310 reference statements)

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“…Gene ontology analysis revealed that biological process of the OMRGs was enriched in the genes enriched at bone mineralization, like down-regulated S1PR1, and up-regulated TWIST1 and PHOSPHO1. Intriguingly, these genes have been shown to target bone formation and bone matrix mineralization (Isenmann et al, 2009;Dillon et al, 2019;Lewis et al, 2019;Xiao et al, 2019). It is likely that there are multiple genes involved in infection-induced changes in bone remodeling, but the relative importance of these distinct genes in bone remodeling during infection remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

NF-κB/TWIST1 Mediates Migration and Phagocytosis of Macrophages in the Mice Model of Implant-Associated Staphylococcus aureus Osteomyelitis

et al. 2020

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Staphylococcus aureus (S. aureus) infection-induced osteomyelitis is a great challenge in clinic treatment. Identification of the essential genes and biological processes that are specifically changed in mononuclear cells at an early stage of S. aureus osteomyelitis is of great clinical significance. Based on transcriptional dataset GSE16129 available publicly, a bioinformatic analysis was performed to identify the differentially expressed genes of osteomyelitis caused by S. aureus infection. ERBB2, TWIST1, and NANOG were screened out as the most valuable osteomyelitis-related genes (OMRGs). A mice model of implant-associated S. aureus osteomyelitis was used to verify the above genes. We found significantly up-regulated expression of TWIST1 in macrophages and accumulation of macrophages around the infected implant. Meanwhile, S. aureus infection increased the expression of TWIST1, MMP9, and MMP13, and stimulated the migration and phagocytosis function of Raw 264.7 cells. Additionally, knock-down of the expression of TWIST1 by siRNA could significantly down-regulate MMP9 and MMP13 and suppress the migration and phagocytosis ability of macrophages in response to S. aureus infection. Furthermore, we found that NF-κB signaling was activated in Raw 264.7 cells by S. aureus and that inhibition of NF-κB signaling by Bay11-7082 blocked the expression of TWIST1, MMP9, and MMP13 as well as cell migration and phagocytosis evoked by S. aureus. Our findings demonstrate that NF-κB/TWIST1 is necessary for migration and phagocytosis of macrophages in response to S. aureus infection. Our study highlights the essential role of NF-κB/TWIST1 in early innate immune response to S. aureus infection in bone.

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Section: Discussionmentioning

confidence: 99%

NF-κB/TWIST1 Mediates Migration and Phagocytosis of Macrophages in the Mice Model of Implant-Associated Staphylococcus aureus Osteomyelitis

et al. 2020

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“…The similarities of the phenotype described here to that of the Phospho1 -/mouse are clear. As discussed above, ablation of PHOSPHO1 in mice induces hypomineralization in young animals, resulting in rickets/osteomalacia and biomechanical deficiency (9)(10)(11) . Here we report that 4-week Enpp6 -/tibiae exhibit hypomineralized trabecular bone compared with controls, along with a significant increase in SMI indicating a change in trabecular geometry.…”

Section: Accepted Articlementioning

confidence: 92%

“…The biochemical mechanisms through which P i is generated within MVs are currently unclear. Orphan phosphatase 1 (PHOSPHO1; Phospho1) was identified as a novel bone phosphatase critical for mineralization (7)(8)(9) . The PHOSPHO1 knock-out mouse (Phospho1 -/-) displays a hypomineralized skeleton at birth, biomechanical incompetency, scoliosis, and spontaneous greenstick fractures (10,11) .…”

Section: Introductionmentioning

confidence: 99%

“…The current leading model for intravesicular PHOSPHO1 function involves the chemical transformation of vesicle membrane constituent phospholipids into appropriate enzymatic substrates for PHOSPHO1 (3,16) . An as-yet unidentified enzyme (or group of enzymes) with phospholipase A 2 activity is first hypothesized to convert membrane-constituent phosphatidylcholine to lysophosphatidylcholine (9,16) . Several vertebrate PLA 2 isoforms are known to be expressed by chondrocytes and osteoblasts and were localized to actively mineralizing matrix in cartilage and metaphyseal bone (17,18) .…”

Section: Introductionmentioning

confidence: 99%

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Ablation of Enpp6 Results in Transient Bone Hypomineralization

et al. 2020

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Biomineralization is a fundamental process key to the development of the skeleton. The phosphatase orphan phosphatase 1 (PHOSPHO1), which likely functions within extracellular matrix vesicles, has emerged as a critical regulator of biomineralization. The biochemical pathways which generate intravesicular PHOSPHO1 substrates are however currently unknown. We hypothesized that the enzyme ectonucleotide pyrophosphatase/phosphodiesterase (ENPP6) is an upstream source of PHOSPHO1 substrate. To test this, we characterized skeletal phenotypes of mice homozygous for a targeted deletion of Enpp6 (Enpp6-/-). Micro-computed tomography of the trabecular compartment revealed transient hypomineralization in Enpp6-/tibiae (p < 0.05) that normalized by 12 weeks of Accepted Article This article is protected by copyright. All rights reserved. This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/jbm4.10439 age. Whole-bone cortical analysis also revealed significantly hypomineralized proximal bone in 4-but not 12-week old Enpp6-/mice (p < 0.05) compared to wild-type animals. Backscattered scanning electron microscopy revealed a failure in 4-week-old trabecular bone of mineralization foci to propagate. Static histomorphometry revealed increased osteoid volume (p>0.01) and osteoid surface (p < 0.05) which recovered by 12 weeks but was not accompanied by changes in osteoblast or osteoclast number. This study is the first to characterize the skeletal phenotype of Enpp6-/mice, revealing transient hypomineralization in young animals compared to wild-type controls. These data suggest that ENPP6 is important for bone mineralization and may function upstream of PHOSPHO1 as a novel means of generating its substrates inside matrix vesicles.

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“…PHOSPHO1 initiates the hydrolysis of intravesicular metabolites including phosphoethanolamine and phosphocholine to obtain P i . Thus, it has been suggested that PHOSPHO1 functions synergistically with TNAP to accumulate P i into the calcified matrix vesicles [ 57 ]. Moreover supplementation of a PHOSPHO1 inhibitor alone and in combination with a TNAP inhibitor, prevented in vitro VSMC calcification [ 58 ].…”

Section: Purinergic Receptor Independent Pathwaymentioning

confidence: 99%

Extracellular Nucleotides Regulate Arterial Calcification by Activating Both Independent and Dependent Purinergic Receptor Signaling Pathways

Opdebeeck

Orriss

Neven

et al. 2020

IJMS

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Arterial calcification, the deposition of calcium-phosphate crystals in the extracellular matrix, resembles physiological bone mineralization. It is well-known that extracellular nucleotides regulate bone homeostasis raising an emerging interest in the role of these molecules on arterial calcification. The purinergic independent pathway involves the enzymes ecto-nucleotide pyrophosphatase/phosphodiesterases (NPPs), ecto-nucleoside triphosphate diphosphohydrolases (NTPDases), 5′-nucleotidase and alkaline phosphatase. These regulate the production and breakdown of the calcification inhibitor—pyrophosphate and the calcification stimulator—inorganic phosphate, from extracellular nucleotides. Maintaining ecto-nucleotidase activities in a well-defined range is indispensable as enzymatic hyper- and hypo-expression has been linked to arterial calcification. The purinergic signaling dependent pathway focusses on the activation of purinergic receptors (P1, P2X and P2Y) by extracellular nucleotides. These receptors influence arterial calcification by interfering with the key molecular mechanisms underlying this pathology, including the osteogenic switch and apoptosis of vascular cells and possibly, by favoring the phenotypic switch of vascular cells towards an adipogenic phenotype, a recent, novel hypothesis explaining the systemic prevention of arterial calcification. Selective compounds influencing the activity of ecto-nucleotidases and purinergic receptors, have recently been developed to treat arterial calcification. However, adverse side-effects on bone mineralization are possible as these compounds reasonably could interfere with physiological bone mineralization.

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How To Build a Bone: PHOSPHO1, Biomineralization, and Beyond

Cited by 50 publications

References 156 publications

NF-κB/TWIST1 Mediates Migration and Phagocytosis of Macrophages in the Mice Model of Implant-Associated Staphylococcus aureus Osteomyelitis

NF-κB/TWIST1 Mediates Migration and Phagocytosis of Macrophages in the Mice Model of Implant-Associated Staphylococcus aureus Osteomyelitis

Ablation of Enpp6 Results in Transient Bone Hypomineralization

Extracellular Nucleotides Regulate Arterial Calcification by Activating Both Independent and Dependent Purinergic Receptor Signaling Pathways

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