ORCID Profile
0000-0001-6850-1723
Current Organisations
University of Florida
,
University of Western Australia
,
Florida Museum of Natural History
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Industrial molecular engineering of nucleic acids and proteins | Industrial biotechnology | Nanobiotechnology
ANZSRC Socio-Economic Objective (SEO)
Related Links
Publications
High-resolution visualization and quantification of nucleic acid-based therapeutics in cells and tissues using Nanoscale secondary ion mass spectrometry (NanoSIMS)
Publisher: Oxford University Press (OUP)
Date: 04-12-2021
DOI: 10.1093/NAR/GKAA1112
Abstract: Nucleic acid therapeutics (NATs) have proven useful in promoting the degradation of specific transcripts, modifying gene expression, and regulating mRNA splicing. In each situation, efficient delivery of nucleic acids to cells, tissues and intracellular compartments is crucial—both for optimizing efficacy and reducing side effects. Despite successes in NATs, our understanding of their cellular uptake and distribution in tissues is limited. Current methods have yielded insights into distribution of NATs within cells and tissues, but the sensitivity and resolution of these approaches are limited. Here, we show that nanoscale secondary ion mass spectrometry (NanoSIMS) imaging can be used to define the distribution of 5-bromo-2′-deoxythymidine (5-BrdT) modified antisense oligonucleotides (ASO) in cells and tissues with high sensitivity and spatial resolution. This approach makes it possible to define ASO uptake and distribution in different subcellular compartments and to quantify the impact of targeting ligands designed to promote ASO uptake by cells. Our studies showed that phosphorothioate ASOs are associated with filopodia and the inner nuclear membrane in cultured cells, and also revealed substantial cellular and subcellular heterogeneity of ASO uptake in mouse tissues. NanoSIMS imaging represents a significant advance in visualizing uptake and distribution of NATs this approach will be useful in optimizing efficacy and delivery of NATs for treating human disease.
Decellularized allogeneic intervertebral disc natural biomaterials for regenerating disc degeneration
Publisher: Impact Journals, LLC
Date: 25-02-2016
Achyranthes bidentata polysaccharide suppresses osteoclastogenesis and bone resorption via inhibiting RANKL signaling
Publisher: Wiley
Date: 09-03-2018
DOI: 10.1002/JCB.26682
Abstract: Osteoclasts are highly differentiated multinucleated giant cells that play fundamental roles in bone resorption and in the pathogenesis of osteolytic conditions, such as osteoporosis and cancer‐induced bone loss. Achyranthes bidentata polysaccharide (ABP) is a hydrophilic compound with anti‐oxidation and anti‐aging characteristics. The impact of ABP on RANKL‐induced osteoclast formation and bone resorption has not been assessed, hence, in this study we investigated the effect of ABP on osteoclast formation and resorption in murine bone marrow derived osteoclasts. We found that ABP was able to suppress RANKL‐induced osteoclast differentiation and bone resorption activity at concentrations above 6.5 µM, while demonstrating no cytotoxicity at concentrations up to 10 µM. The actions of ABP were mediated through inhibition of RANKL‐induced c‐Fos and NFATc1 gene and protein expression. Furthermore, we found that ABP suppressed NFATc1 transcriptional activity, and the phosphorylation of MAPK pathways induced by RANKL. Collectively, ABP attenuates RANKL‐mediated osteoclast activity and signaling, and might serve as a potential therapeutic candidate for preventing bone loss related diseases.
Subcellular Partitioning of Arsenic Trioxide Revealed by Label-Free Imaging
Publisher: American Chemical Society (ACS)
Date: 03-10-2022
DOI: 10.1021/ACS.ANALCHEM.2C02770
Abstract: Subcellular partitioning of therapeutic agents is highly relevant to their interactions with target molecules and drug efficacy, but studying subcellular partitioning is an enormous challenge. Here, we describe the application of nanoscale secondary ion mass spectrometry (NanoSIMS) analysis to define the subcellular pharmacokinetics of a cytotoxic chemotherapy drug, arsenic trioxide (ATO). We reasoned that defining the partitioning of ATO would yield valuable insights into the mechanisms underlying ATO efficacy. NanoSIMS imaging made it possible to define the intracellular fate of ATO in a label-free manner─and with high resolution and high sensitivity. Our studies of ATO-treated cells revealed that arsenic accumulates in the nucleolus. After prolonged ATO exposure, ∼40 nm arsenic- and sulfur-rich protein aggregates appeared in the cell nucleolus, nucleus, and membrane-free compartments in the cytoplasm, and our studies suggested that the partitioning of nanoscale aggregates could be relevant to cell survival. All-trans retinoic acid increased intracellular ATO levels and accelerated the nanoscale aggregate formation in the nucleolus. This study yielded fresh insights into the subcellular pharmacokinetics of an important cancer therapeutic agent and the potential impact of drug partitioning and pharmacokinetics on drug activity.
Evolution and Diversification Dynamics of Butterflies
Publisher: Cold Spring Harbor Laboratory
Date: 19-05-2022
DOI: 10.1101/2022.05.17.491528
Abstract: Butterflies are a erse and charismatic insect group that are thought to have ersified via coevolution with plants and in response to dispersals following key geological events. These hypotheses have been poorly tested at the macroevolutionary scale because a comprehensive phylogenetic framework and datasets on global distributions and larval hosts of butterflies are lacking. We sequenced 391 genes from nearly 2,000 butterfly species to construct a new, phylogenomic tree of butterflies representing 92% of all genera and aggregated global distribution records and larval host datasets. We found that butterflies likely originated in what is now the Americas, ∼100 Ma, shortly before the Cretaceous Thermal Maximum, then crossed Beringia and ersified in the Paleotropics. The ancestor of modern butterflies likely fed on Fabaceae, and most extant families were present before the K/Pg extinction. The majority of butterfly dispersals occurred from the tropics (especially the Neotropics) to temperate zones, largely supporting a “cradle” pattern of ersification. Surprisingly, host breadth changes and shifts to novel host plants had only modest impacts.
Astilbin prevents bone loss in ovariectomized mice through the inhibition of RANKL-induced osteoclastogenesis
Publisher: Wiley
Date: 11-10-2019
DOI: 10.1111/JCMM.14713
Femorofemoral bypass allowed limb preservation after late diagnosis of left common iliac artery thrombosis due to blunt trauma
Publisher: SAGE Publications
Date: 2015
Abstract: Acute common iliac artery occlusion which results from blunt abdominal trauma is rare and potentially leads to a late diagnosis. We report a case of a 58-year-old patient who suffered a late diagnosed acute left common iliac artery occlusion secondary to abdominal trauma. An emergency exploratory laparotomy was performed to stop intra-abdominal bleeding, while his left limb ischemia was not noticed until 32 h later and femorofemoral bypass was then successfully performed for revascularization. Compartment syndrome was observed postoperatively, and fasciotomy was performed promptly. The wound was temporarily covered with Vaccum Sealing Drainage due to high skin tension. Patient underwent skin-grafting after leg swelling subsided. The follow-up turned out that these managements were valid in the preservation of the limb viability. This case highlights the prudent recognition of the acute lower extremity ischemia in the abdominal trauma and immediate remedy for acute iliac artery occlusion after a late diagnosis.
Fumitremorgin C Attenuates Osteoclast Formation and Function via Suppressing RANKL-Induced Signaling Pathways
Publisher: Frontiers Media SA
Date: 10-03-2020
Decellularized periosteum as a potential biologic scaffold for bone tissue engineering
Publisher: Elsevier BV
Date: 06-2015
DOI: 10.1016/J.ACTBIO.2015.02.020
Abstract: Bone grafting or bone substitute is typically used to bridge a bone defect that has been caused by trauma, tumor resection, pathological degeneration, or congenital deformations. However, bone graft healing and remodeling is always a major concern of orthopedic surgeons. Because the periosteum has a remarkable regenerative capacity and is widely recognized to be essential for the initiation of bone graft healing and remodeling, the present study aimed to produce a rabbit decellularized periosteum (D-periosteum) to be used as a biologic scaffold for future bone tissue engineering. We obtained the D-periosteum by employing a combination of commonly used decellularization processes, which include physical methods as well as chemical and enzymatic solutions. The cellular components were effectively removed, and this removal was demonstrated using current decellularization criteria (H&E staining, DAPI staining, DNA quantification and agarose gel electrophoresis) however, there were no significant alterations of the native extracellular matrix (ECM) properties (collagen, glycosaminoglycan (GAG), microarchitecture and mechanical properties). Periosteum-derived cells (PDCs) could adhere, proliferate and infiltrate into the D-periosteum in vitro. The allogenic D-periosteum was implanted subcutaneously into the backs of rabbits over 28 days to study the biocompatibility in vivo. The D-periosteum did not elicit a severe immunogenic response. In summary, a biologic scaffold composed of ECM from periosteum has been successfully developed. The D-periosteum maintains biocompatibility in vitro and in vivo and, therefore, can provide a naturally compatible scaffold for use in future bone tissue engineering.
Helvolic acid attenuates osteoclast formation and function via suppressing RANKL-induced NFATc1 activation
Publisher: Wiley
Date: 20-10-2019
DOI: 10.1002/JCP.27385
Abstract: Excessive osteoclast formation and function are considered as the main causes of bone lytic disorders such as osteoporosis and osteolysis. Therefore, the osteoclast is a potential therapeutic target for the treatment of osteoporosis or other osteoclast‐related diseases. Helvolic acid (HA), a mycotoxin originally isolated from Aspergillus fumigatus , has been discovered as an effective broad‐spectrum antibacterial agent and has a wide range of pharmacological properties. Herein, for the first time, HA was demonstrated to be capable of significantly inhibiting receptor activator of nuclear factor‐κB ligand (RANKL)‐induced osteoclastogenesis and bone resorption in vitro by suppressing nuclear factor of activated T cells 1 (NFATc1) activation. This inhibition was followed by the dramatically decreased expression of NFATc1‐targeted genes including Ctr (encoding calcitonin receptor), Acp5 (encoding tartrate‐resistant acid phosphatase [TRAcP]), Ctsk (encoding cathepsin K), Atp6v0d2 (encoding the vacuolar H+ ATPase V0 subunit d2 [V‐ATPase‐d2]) and Mmp9 (encoding matrix metallopeptidase 9) which are osteoclastic‐specific genes required for osteoclast formation and function. Mechanistically, HA was shown to greatly attenuate multiple upstream pathways including extracellular signal‐regulated kinase (ERK) phosphorylation, c‐Fos signaling, and intracellular Ca 2+ oscillation, but had little effect on nuclear factor‐κB (NF‐κB) activation. In addition, HA also diminished the RANKL‐induced generation of intracellular reactive oxygen species. Taken together, our study indicated HA effectively suppressed RANKL‐induced osteoclast formation and function. Thus, we propose that HA can be potentially used in the development of a novel drug for osteoclast‐related bone diseases.
Roburic acid attenuates osteoclastogenesis and bone resorption by targeting RANKL-induced intracellular signaling pathways
Publisher: Wiley
Date: 19-11-2022
DOI: 10.1002/JCP.30642
Abstract: Excessive activity of osteoclasts contributes to skeletal diseases such as osteoporosis and osteolysis. However, current drugs targeting osteoclast have various deficiencies, placing natural compounds as substitutions of great potential. Roburic acid (RA) is a triterpenoid exacted from Radix Gentianae Macrophyllae, which exhibits inhibitory effects on inflammation and oxidation. By employing an in vitro osteoclastogenesis model, this study investigates the effects and mechanisms of RA on intracellular signaling induced by receptor activator of nuclear factor‐κB ligand (RANKL). As expected, RA at a concentration scope from 1 to 10 μM d ened the osteoclast differentiation of bone marrow macrophages (BMMs) but without cell toxicity. Interestingly, RA showed no effect on osteoblastogenesis in vitro. Furthermore, RA mitigated F‐actin ring formation, hydroxyapatite resorption, and gene expression in osteoclasts. Mechanistically, RA suppressed TNF receptor‐associated factor 6 (TRAF6), the crucial adaptor protein following RANKL‐RANK binding. On the one hand, RA downregulated the nuclear factor‐κB (NF‐κB) activity, extracellular regulated protein kinases (ERK) phosphorylation, and calcium oscillations. On the other hand, RA upregulated the antioxidative response element (ARE) response and the protein expression of heme oxygenase (HO)‐1. These upstream alterations eventually led to the suppression of the nuclear factor of activated T cells 1 (NFATc1) activity and the expression of proteins involved in osteoclastogenesis and bone resorption. Furthermore, by using an ovariectomized (OVX) mice model, RA was found to have therapeutic effects against bone loss. On account of these findings, RA could be used to restrain osteoclasts for treating osteoporosis and other osteolytic diseases.
Epithelioid angiosarcoma of the spine: A case report of a rare bone tumor
Publisher: Spandidos Publications
Date: 09-04-2014
DOI: 10.3892/OL.2014.2055
Obacunone targets macrophage migration inhibitory factor (MIF) to impede osteoclastogenesis and alleviate ovariectomy-induced bone loss
Publisher: Elsevier BV
Date: 11-2023
Asperpyrone A attenuates RANKL‐induced osteoclast formation through inhibiting NFATc1, Ca2+ signalling and oxidative stress
Publisher: Wiley
Date: 15-10-2019
DOI: 10.1111/JCMM.14700
Cytochalasin Z11 inhibits RANKL-induced osteoclastogenesis
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C9RA07240C
Abstract: CytoZ11 was demonstrated to inhibit RANKL-induced osteoclast formation and function by affecting NFATc1 activation. This is achieved by the suppression of c-Fos and NF-κB pathways. Therefore, CytoZ11 may serve as a promising therapy for osteoclast-related bone disorders.
Thiaplakortone B attenuates RANKL‐induced NF‐κB and MAPK signaling and dampens OVX‐induced bone loss in mice
Publisher: Elsevier BV
Date: 10-2022
DOI: 10.1016/J.BIOPHA.2022.113622
Abstract: Osteoclasts play an important role in maintaining the relative stability of bone mass. Abnormal number and function of osteoclasts are closely related to osteoporosis and osteolytic diseases. Thiaplakortone B (TPB), a natural compound derived from the Great Barrier Reef sponge Plakortis lita, has been reported to inhibit the growth of the malaria parasite, Plasmodium falciparum, but its effect on osteoclastogenesis has not been previously investigated. In our study, we found that TPB suppresses the receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclast formation and resorption activity by tartrate-resistant acid phosphatase (TRAcP) staining, immunofluorescence staining of F-actin belts and hydroxyapatite resorption assay. Furthermore, using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting analysis, we discovered that TPB inhibits osteoclast-specific genes and proteins expression. Mechanistically, TPB blocks multiple upstream pathways including calcium oscillation, NF-κB, mitogen-activated protein kinase (MAPK) and nuclear factor of activated T cells 1(NFATc1) signaling pathways. In vivo, TPB could d en bone loss in an ovariectomy (OVX) mouse model by micro-CT assessment and histological staining. Therefore, TPB may serve as a potential therapeutic candidate for the treatment of osteoporosis and osteolysis.
Osteoblast-derived EGFL6 couples angiogenesis to osteogenesis during bone repair
Publisher: Ivyspring International Publisher
Date: 2021
DOI: 10.7150/THNO.60902
Modulating calcium-mediated NFATc1 and mitogen-activated protein kinase deactivation underlies the inhibitory effects of kavain on osteoclastogenesis and bone resorption
Publisher: Wiley
Date: 04-08-2018
DOI: 10.1002/JCP.26893
Abstract: Osteoclasts are responsible for bone resorption during the process of bone remodeling. Increased osteoclast numbers and bone resorption activity are the main factors contributing to bone loss–related diseases such as osteoporosis. Therefore, modulating the formation and function of osteoclasts is critical for the effective treatment of osteolysis and osteoporosis. Kavain is the active ingredient extracted from the root of the kava plant, which possesses known anti‐inflammatory properties. However, the effects of kavain on osteoclastogenesis and bone resorption remain unclear. In this study, we found that kavain inhibits receptor activator of nuclear factor‐κB ligand (RANKL)–induced osteoclast differentiation and fusion using tartrate‐resistant acid phosphatase staining and immunofluorescence. Furthermore, kavain inhibited bone resorption performed by osteoclasts. Using reverse transcription‐polymerase chain reaction and western blot analysis, we found that kavain downregulates the expression of osteoclast marker genes, such as nuclear factor of activated T cells, cytoplasmic 1 ( Nfatc1 ), v‐atpase d2 ( Atp6v0d2 ), dendrocyte expressed seven transmembrane protein ( Dcst ), matrix metallopeptidase 9 ( Mmp9 ), cathepsin K ( Ctsk ), and Acp5 . Additionally, kavain repressed RANKL‐induced calcium oscillations, nuclear factor of activated T cells activation, and mitogen‐activated protein kinase phosphorylation, while leaving NF‐κB unaffected. We found no effects of kavain on either osteoblast proliferation or differentiation. Besides, kavain inhibited bone loss in ovariectomized mice by suppressing osteoclastogenesis. Collectively, these data suggest a potential use for kavain as a candidate drug for the treatment of osteolytic diseases.
Loureirin B suppresses RANKL-induced osteoclastogenesis and ovariectomized osteoporosis via attenuating NFATc1 and ROS activities
Publisher: Ivyspring International Publisher
Date: 2019
DOI: 10.7150/THNO.35414
Periosteal matrix-derived hydrogel promotes bone repair through an early immune regulation coupled with enhanced angio- and osteogenesis
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.BIOMATERIALS.2019.119552
Abstract: Bone healing is a complex physiological process initiated by early regulation of the inflammatory immunity and entails multiple events including angiogenesis, osteogenic differentiation, and biomineralization. Here, we fabricated an injectable periosteal extracellular matrix (PEM) hydrogel that dynamically integrates multiple biological functions and, therefore, acts at different stages of the fracture healing process. PEM hydrogels were fully characterized compared with a collagen I hydrogel. The effects of PEM hydrogels on the different phases of the healing process were assessed in vitro. PEM hydrogels induced the recruitment and M2-polarization of macrophages, promoted the differentiation of MSCs into endothelial-like cells, HUVEC tube formation, osteogenic differentiation of primary calvarial osteoblasts and MSCs, and mineralization after being immersed in simulated body fluid. The dynamic and multiphase effects of the hydrogels were evaluated using a rat critical-sized calvarial defect model in vivo. During the early phase of repair, PEM hydrogels facilitated the M1-to-M2 transition of macrophages. As bone repair progressed, PEM hydrogels promoted blood vessel migration, the development of relative larger blood vessels, and functional vascularization. These effects were also verified in a subcutaneous embedding model. Eventually, PEM hydrogels promoted mature bone formation in large bone defects to a greater extent than collagen I hydrogels. These biological effects coordinated well with the natural process of bone regeneration. Thus, PEM hydrogels may serve as promising biomaterials in bone tissue engineering.
Evodiamine inhibits RANKL-induced osteoclastogenesis and prevents ovariectomy-induced bone loss in mice
Publisher: Wiley
Date: 19-11-2019
DOI: 10.1111/JCMM.13955
Inhibitory Effects of Rhaponticin on Osteoclast Formation and Resorption by Targeting RANKL-Induced NFATc1 and ROS Activity
Publisher: Frontiers Media SA
Date: 23-09-2021
DOI: 10.3389/FPHAR.2021.645140
Abstract: The extravagant osteoclast formation and resorption is the main cause of osteoporosis. Inhibiting the hyperactive osteoclastic resorption is considered as an efficient treatment for osteoporosis. Rhaponticin (RH) is a small molecule that has been reported to possess anti-inflammatory, anti-allergic, anti-fibrotic, and anti-diabetic activities. However, the influence of RH on osteoclasts differentiation and function is still unclear. To this end, an array of assays including receptor activator of nuclear factor kappa-Β (NF-κB) ligand (RANKL) induced osteoclastogenesis, tartrate-resistant acidic phosphatase (TRAcP) staining, immunofluorescence, and hydroxyapatite resorption were performed in this study. It was found that RH had significant anti-catabolic effects by inhibiting osteoclastogenesis and bone resorption without cytotoxicity. Mechanistically, the expression of NADPH oxidase 1 (Nox1) was found to be suppressed and antioxidant enzymes including catalase, superoxide dismutase 2 (SOD-2), and heme oxygenase-1(HO-1) were enhanced following RH treatment, suggesting RH exhibited antioxidant activity by reducing the generation of reactive oxygen species (ROS) as well as enhancing the depletion of ROS. In addition, MAPKs, NF-κB, and intracellular Ca 2+ oscillation pathways were significantly inhibited by RH. These changes led to the deactivation of osteoclast master transcriptional factor-nuclear factor of activated T cells 1 (NFATc1), as examined by qPCR and Western blot assay, which led to the decreased expression of downstream integrin β3, c-Fos, cathepsin K, and Atp6v0d2. These results suggested that RH could effectively suppress RANKL-regulated osteoclast formation and bone resorption. Therefore, we propose that RH can represent a novel natural small molecule for the treatment of osteoporosis by inhibiting excessive osteoclast activity.
Therapeutic anabolic and anticatabolic benefits of natural Chinese medicines for the treatment of osteoporosis
Publisher: Frontiers Media SA
Date: 25-11-2019
Calmodulin interacts with Rab3D and modulates osteoclastic bone resorption
Publisher: Springer Science and Business Media LLC
Date: 29-11-2016
DOI: 10.1038/SREP37963
Abstract: Calmodulin is a highly versatile protein that regulates intracellular calcium homeostasis and is involved in a variety of cellular functions including cardiac excitability, synaptic plasticity and signaling transduction. During osteoclastic bone resorption, calmodulin has been reported to concentrate at the ruffled border membrane of osteoclasts where it is thought to modulate bone resorption activity in response to calcium. Here we report an interaction between calmodulin and Rab3D, a small exocytic GTPase and established regulator osteoclastic bone resorption. Using yeast two-hybrid screening together with a series of protein-protein interaction studies, we show that calmodulin interacts with Rab3D in a calcium dependent manner. Consistently, expression of a calcium insensitive form of calmodulin (i.e. CaM1234) perturbs calmodulin-Rab3D interaction as monitored by bioluminescence resonance energy transfer (BRET) assays. In osteoclasts, calmodulin and Rab3D are constitutively co-expressed during RANKL-induced osteoclast differentiation, co-occupy plasma membrane fractions by differential gradient sedimentation assay and colocalise in the ruffled border as revealed by confocal microscopy. Further, functional blockade of calmodulin-Rab3D interaction by calmidazolium chloride coincides with an attenuation of osteoclastic bone resorption. Our data imply that calmodulin- Rab3D interaction is required for efficient bone resorption by osteoclasts in vitro .
A missense mutation sheds light on a novel structure–function relationship of RANKL
Publisher: Wiley
Date: 23-09-2021
DOI: 10.1002/JCP.30045
Abstract: The tumor necrosis factor (TNF)‐like core domain of receptor activator of nuclear factor‐κB ligand (RANKL) is a functional domain critical for osteoclast differentiation. One of the missense mutations identified in patients with osteoclast‐poor autosomal recessive osteopetrosis (ARO) is located in residue methionine 199 that is replaced with lysine (M199K) amid the TNF‐like core domain. However, the structure–function relationship of this mutation is not clear. Sequence‐based alignment revealed that the fragment containing human M199 is highly conserved and equivalent to M200 in rat. Using site‐directed mutagenesis, we generated three recombinant RANKL mutants M200K/A/E (M200s) by replacing the methionine 200 with lysine (M200K), alanine (M200A), and glutamic acid (M200E), representative of distinct physical properties. TRAcP staining and bone pit assay showed that M200s failed to support osteoclast formation and bone resorption, accompanied by impaired osteoclast‐related signal transduction. However, no antagonistic effect was found in M200s against wild‐type rat RANKL. Analysis of the crystal structure of RANKL predicted that this methionine residue is located within the hydrophobic core of the protein, thus, likely to be crucial for protein folding and stability. Consistently, differential scanning fluorimetry analysis suggested that M200s were less stable. Western blot analysis analyses further revealed impaired RANKL trimerization by M200s. Furthermore, receptor–ligand binding assay displayed interrupted interaction of M200s to its intrinsic receptors. Collectively, our studies revealed the molecular basis of human M199‐induced ARO and elucidated the indispensable role of rodent residue M200 (equivalent to human M199) for the RANKL function.
Sugar transporter Slc37a2 regulates bone metabolism in mice via a tubular lysosomal network in osteoclasts
Publisher: Springer Science and Business Media LLC
Date: 21-02-2023
DOI: 10.1038/S41467-023-36484-2
Abstract: Osteoclasts are giant bone-digesting cells that harbor specialized lysosome-related organelles termed secretory lysosomes (SLs). SLs store cathepsin K and serve as a membrane precursor to the ruffled border, the osteoclast’s ‘resorptive apparatus’. Yet, the molecular composition and spatiotemporal organization of SLs remains incompletely understood. Here, using organelle-resolution proteomics, we identify member a2 of the solute carrier 37 family (Slc37a2) as a SL sugar transporter. We demonstrate in mice that Slc37a2 localizes to the SL limiting membrane and that these organelles adopt a hitherto unnoticed but dynamic tubular network in living osteoclasts that is required for bone digestion. Accordingly, mice lacking Slc37a2 accrue high bone mass owing to uncoupled bone metabolism and disturbances in SL export of monosaccharide sugars, a prerequisite for SL delivery to the bone-lining osteoclast plasma membrane. Thus, Slc37a2 is a physiological component of the osteoclast’s unique secretory organelle and a potential therapeutic target for metabolic bone diseases.
Pseurotin A inhibits osteoclastogenesis and prevents ovariectomized-induced bone loss by suppressing reactive oxygen species
Publisher: Ivyspring International Publisher
Date: 2019
DOI: 10.7150/THNO.30206
Incidence and risk factors of early deep venous thrombosis after varicose vein surgery with routine use of a tourniquet
Publisher: Elsevier BV
Date: 06-2015
DOI: 10.1016/J.THROMRES.2015.03.008
Abstract: The incidence of early deep venous thrombosis (DVT) following varicose vein surgery (traditional open stripping) with routine use of a tourniquet remains unknown. A retrospective analysis of all patients who underwent varicose vein surgery with a tourniquet in the authors' unit between 1 January 2012 and 30 November 2013 was undertaken. Cases of postoperative DVT were identified from the unit database, and re-assessments conducted 1, 3 and 6 months after the initial diagnosis were recorded from the outpatient department. Out of 1461 patients, 113 (7.7%) developed postoperative DVT. Nineteen (1.3%) patients had proximal DVT, and 94 (6.4%) patients had isolated distal DVT. The risk factors for postoperative DVT included old age (≥65 years), female sex and gastrocnemius vein dilation (GVD). GVD was found to be a significant independent risk factor for the occurrence of DVT, with an odds ratio of 2.437 (95% confidence interval 1.644-3.611). Five patients with distal DVT (5.7%) and eight patients with proximal DVT (44.4%) still exhibited a thrombus at 6-month follow-up, but with decreased size and at various stages of resolution. This study found a higher incidence of postoperative DVT (7.7%) with routine use of a tourniquet during varicose vein surgery than has been reported previously. Among the factors examined, GVD had the highest predictive power for postoperative DVT. Both distal and proximal DVT were associated with acceptable outcomes.
Steroid-induced osteonecrosis of the femoral head reveals enhanced reactive oxygen species and hyperactive osteoclasts
Publisher: Ivyspring International Publisher
Date: 2020
DOI: 10.7150/IJBS.40917
NanoSIMS imaging of lipid absorption by intestinal enterocytes
Publisher: Elsevier BV
Date: 11-2022
Intracellular localisation of Mycobacterium tuberculosis affects efficacy of the antibiotic pyrazinamide
Publisher: Springer Science and Business Media LLC
Date: 21-06-2021
DOI: 10.1038/S41467-021-24127-3
Abstract: To be effective, chemotherapy against tuberculosis (TB) must kill the intracellular population of the pathogen, Mycobacterium tuberculosis . However, how host cell microenvironments affect antibiotic accumulation and efficacy remains unclear. Here, we use correlative light, electron, and ion microscopy to investigate how various microenvironments within human macrophages affect the activity of pyrazinamide (PZA), a key antibiotic against TB. We show that PZA accumulates heterogeneously among in idual bacteria in multiple host cell environments. Crucially, PZA accumulation and efficacy is maximal within acidified phagosomes. Bedaquiline, another antibiotic commonly used in combined TB therapy, enhances PZA accumulation via a host cell-mediated mechanism. Thus, intracellular localisation and specific microenvironments affect PZA accumulation and efficacy. Our results may explain the potent in vivo efficacy of PZA, compared to its modest in vitro activity, and its critical contribution to TB combination chemotherapy.
Cycloastragenol Attenuates Osteoclastogenesis and Bone Loss by Targeting RANKL-Induced Nrf2/Keap1/ARE, NF-κB, Calcium, and NFATc1 Pathways
Publisher: Frontiers Media SA
Date: 20-01-2022
DOI: 10.3389/FPHAR.2021.810322
Abstract: Osteoporosis, which typically affects postmenopausal women, is an osteolytic disease due to over-activation of osteoclasts. However, current drugs targeting osteoclast inhibition face various side effects, making natural compounds with great interest as alternative treatment options. Cycloastragenol (CAG) is a triterpenoid with multiple biological activities. Previously, CAG’s activity against aging-related osteoporosis was reported, but the mechanisms of actions for the activities were not understood. This study demonstrated that CAG dose-dependently inhibited osteoclast formation in receptor activator of nuclear factor-κB ligand (RANKL)-stimulated bone marrow macrophage (BMMs). Mechanism studies showed that CAG inhibited NF-κB, calcium, and nuclear factor of activated T cells 1 (NFATc1) pathways. Additionally, CAG also promoted the nuclear factor-erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)/anti-oxidative response element (ARE) pathway that scavenges reactive oxygen species (ROS). Furthermore, CAG was also found to prevent bone loss of postmenopausal osteoporosis (PMO) in a preclinical model of ovariectomized (OVX) mice. Collectively, our research confirms that CAG inhibits the formation and function of osteoclasts by regulating RANKL-induced intracellular signaling pathways, which may represent a promising alternative for the therapy of osteoclast-related disease.
Dracorhodin perchlorate inhibits osteoclastogenesis through repressing RANKL-stimulated NFATc1 activity
Publisher: Wiley
Date: 21-01-2020
DOI: 10.1111/JCMM.15003
The lipoprotein lipase that is shuttled into capillaries by GPIHBP1 enters the glycocalyx where it mediates lipoprotein processing
Publisher: Proceedings of the National Academy of Sciences
Date: 23-10-2023
Smart Nanosacrificial Layer on the Bone Surface Prevents Osteoporosis through Acid-Base Neutralization Regulated Biocascade Effects
Publisher: American Chemical Society (ACS)
Date: 22-09-2020
DOI: 10.1021/JACS.0C07309
Isosinensetin alleviates estrogen deficiency-induced osteoporosis via suppressing ROS-mediated NF-κB/MAPK signaling pathways
Publisher: Elsevier BV
Date: 04-2023
Poria cocos polysaccharide attenuates RANKL-induced osteoclastogenesis by suppressing NFATc1 activity and phosphorylation of ERK and STAT3
Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.ABB.2018.04.011
Abstract: Pathological fractures caused by osteolytic lesions seriously threaten the health of patients. Osteoclasts play important roles in bone resorption whose hyperfunction are closely related to osteolytic lesions. Studies on osteoclast differentiation and function assist in the prevention of excessive bone loss associated diseases. We screened a variety of natural compounds with anti-inflammatory effect and found that poria cocos polysaccharide (PCP) inhibited RANKL-induced osteoclast formation and bone resorption via TRAcP staining, immunofluorescence, RT-PCR and western blot. PCP down-regulated phosphorylation of STAT3, P38, ERK and JNK, and thus repressed the expression of NFAcT1 and c-Fos during RANKL-induced osteoclastogenesis. Besides, the expression of bone resorption related genes such as TRAcP and CTSK was suppressed by PCP. The results suggest that PCP can be invoked as a candidate for the treatment of osteolytic diseases by inhibiting osteoclastogenesis.
Lumichrome inhibits osteoclastogenesis and bone resorption through suppressing RANKL-induced NFAT activation and calcium signaling
Publisher: Wiley
Date: 15-06-2018
DOI: 10.1002/JCP.26841
Abstract: The dynamic balance between bone resorption and bone formation is crucial to maintain bone mass. Osteoclasts are key cells that perform bone resorption while osteoblasts and osteocytes function in bone formation. Osteoporosis, a bone metabolism disease characterized by bone loss and degradation of bone microstructure, occurs when osteoclastic bone resorption outstrips osteoblastic bone synthesis. The interaction between receptor activator of nuclear factor κB ligand (RANKL) and RANK on the surface of bone marrow macrophages promotes osteoclast differentiation and activation. In this study, we found that lumichrome, a photodegradation product of riboflavin, inhibits RANKL‐induced osteoclastogenesis and bone resorption as determined by tartrate‐resistant acid phosphatase staining, immunofluorescence, reverse transcription‐polymerase chain reaction, and western blot. Our results showed that lumichrome represses the expression of osteoclast marker genes, including cathepsin K ( Ctsk ) and Nfatc1 . In addition, lumichrome suppressed RANKL‐induced calcium oscillations, NFATc1, NF‐κB, and MAPK signaling activation. Moreover, lumichrome promoted osteoblast differentiation at an early stage, as demonstrated by upregulated expression of osteoblast marker genes Alp , Runx2 , and Col1a1 . We also found that lumichrome reduces bone loss in ovariectomized mice by inhibiting osteoclastogenesis. In summary, our data suggest the potential of lumichrome as a therapeutic drug for osteolytic diseases.
An emerging role of Prevotella histicola on estrogen deficiency-induced bone loss through the gut microbiota-bone axis in postmenopausal women and in ovariectomized mice
Publisher: Elsevier BV
Date: 10-2021
DOI: 10.1093/AJCN/NQAB194
ADR3, a next generation i-body to human RANKL, inhibits osteoclast formation and bone resorption
Publisher: Elsevier BV
Date: 02-2023
Cistanche deserticola polysaccharide attenuates osteoclastogenesis and bone resorption via inhibiting RANKL signaling and reactive oxygen species production
Publisher: Wiley
Date: 03-07-2018
DOI: 10.1002/JCP.26882
Abstract: Osteoporosis is a metabolic disease characterized by osteopenia and bone microstructural deterioration. Osteoclasts are the primary effector cells that degrade bone matrix and their abnormal function leads to the development of osteoporosis. Reactive oxygen species (ROS) accumulation during cellular metabolism promotes osteoclast proliferation and differentiation, therefore, playing an important role in osteoporosis. Cistanche deserticola polysaccharide (CDP) possesses antitumor, anti‐inflammatory, and antioxidant activity. However, the impact of CDP on osteoclasts is unclear. In this study, tartrate‐resistant acid phosphatase staining, immunofluorescence, reverse transcription‐polymerase chain reaction, and western blot analysis were utilized to demonstrate that CDP inhibited osteoclastogenesis and hydroxyapatite resorption. In addition, CDP also inhibited the expression of osteoclast maker genes including Ctsk , Mmp9 , and Acp5 and had no effect on receptor activator of nuclear factor κB (RANK) expression. Mechanistic analyses revealed that CDP increases the expression of antioxidant enzymes to attenuate RANKL‐mediated ROS production in osteoclasts and inhibits nuclear factor of activated T cells and mitogen‐activated protein kinase activation. These results suggest that CDP may represent a candidate drug for the treatment of osteoporosis caused by excessive osteoclast activity.
Related Organisations
C. A. Triplehorn Insect Collection
Location: United States of America
Related Funding Activities
Early Career Industry Fellowships - Grant ID: IE230100042
Start Date: 07-2023
End Date: 06-2026
Amount: $462,846.00
Funder: Australian Research Council
View Funded Activity