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Dive into the research topics where Julie C. Crockett is active.

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Featured researches published by Julie C. Crockett.


Bone | 2011

Biochemical and molecular mechanisms of action of bisphosphonates

Michael J. Rogers; Julie C. Crockett; Fraser P. Coxon; Jukka Mönkkönen

This review describes the key discoveries over the last 15 years that have led to a clearer understanding of the molecular mechanisms by which bisphosphonate drugs inhibit bone resorption. Once released from bone mineral surfaces during bone resorption, these agents accumulate intracellularly in osteoclasts. Simple bisphosphonates such as clodronate are incorporated into non-hydrolysable analogues of adenosine triphosphate, which induce osteoclast apoptosis. The considerably more potent nitrogen-containing bisphosphonates are not metabolised but potently inhibit farnesyl pyrophosphate (FPP) synthase, a key enzyme of the mevalonate pathway. This prevents the synthesis of isoprenoid lipids necessary for the post-translational prenylation of small GTPases, thereby disrupting the subcellular localisation and normal function of these essential signalling proteins. Inhibition of FPP synthase also results in the accumulation of the upstream metabolite isopentenyl diphosphate, which is incorporated into the toxic nucleotide metabolite ApppI. Together, these properties explain the ability of bisphosphonate drugs to inhibit bone resorption by disrupting osteoclast function and survival. These discoveries are also giving insights into some of the adverse effects of bisphosphonates, such as the acute phase reaction that is triggered by inhibition of FPP synthase in peripheral blood monocytes.


Journal of Cell Science | 2011

Bone remodelling at a glance

Julie C. Crockett; Michael J. Rogers; Fraser P. Coxon; Lynne J. Hocking; Miep H. Helfrich

The bone remodelling cycle (see Poster panel “The bone remodelling cycle”) maintains the integrity of the skeleton through the balanced activities of its constituent cell types. These are the bone-forming osteoblast, a cell that produces the organic bone matrix and aids its mineralisation ([


American Journal of Human Genetics | 2008

Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations.

Matteo M Guerrini; Cristina Sobacchi; Barbara Cassani; Mario Abinun; Sara Sebnem Kilic; Alessandra Pangrazio; Daniele Moratto; Evelina Mazzolari; Jill Clayton-Smith; Paul J. Orchard; Fraser P. Coxon; Miep H. Helfrich; Julie C. Crockett; David Mellis; Ashok Vellodi; Ilhan Tezcan; Luigi D. Notarangelo; Michael J. Rogers; Paolo Vezzoni; Anna Villa; Annalisa Frattini

Autosomal-Recessive Osteopetrosis (ARO) comprises a heterogeneous group of bone diseases for which mutations in five genes are known as causative. Most ARO are classified as osteoclast-rich, but recently a subset of osteoclast-poor ARO has been recognized as due to a defect in TNFSF11 (also called RANKL or TRANCE, coding for the RANKL protein), a master gene driving osteoclast differentiation along the RANKL-RANK axis. RANKL and RANK (coded for by the TNFRSF11A gene) also play a role in the immune system, which raises the possibility that defects in this pathway might cause osteopetrosis with immunodeficiency. From a large series of ARO patients we selected a Turkish consanguineous family with two siblings affected by ARO and hypogammaglobulinemia with no defects in known osteopetrosis genes. Sequencing of genes involved in the RANKL downstream pathway identified a homozygous mutation in the TNFRSF11A gene in both siblings. Their monocytes failed to differentiate in vitro into osteoclasts upon exposure to M-CSF and RANKL, in keeping with an osteoclast-intrinsic defect. Immunological analysis showed that their hypogammaglobulinemia was associated with impairment in immunoglobulin-secreting B cells. Investigation of other patients revealed a defect in both TNFRSF11A alleles in six additional, unrelated families. Our results indicate that TNFRSF11A mutations can cause a clinical condition in which severe ARO is associated with an immunoglobulin-production defect.


Molecular Pharmacology | 2006

Cytosolic entry of bisphosphonate drugs requires acidification of vesicles after fluid-phase endocytosis.

Kg Thompson; Michael J. Rogers; Fraser P. Coxon; Julie C. Crockett

Bisphosphonates such as alendronate and zoledronate are blockbuster drugs used to inhibit osteoclast-mediated bone resorption. Although the molecular mechanisms by which bisphosphonates affect osteoclasts are now evident, the exact route by which they are internalized by cells is not known. To clarify this, we synthesized a novel, fluorescently labeled analog of alendronate (AF-ALN). AF-ALN was rapidly internalized into intracellular vesicles in J774 macrophages and rabbit osteoclasts; uptake of AF-ALN or [14C]zoledronate was stimulated by the presence of Ca2+ and Sr2+ and could be inhibited by addition of EGTA or clodronate, both of which chelate calcium ions. Both EGTA and clodronate also prevented the bisphosphonate-induced inhibition of Rap1A prenylation, an effect that was reversed by addition of Ca2+. In J774 cells and osteoclasts, vesicular AF-ALN colocalized with dextran (but not wheat germ agglutinin or transferrin), and uptake of AF-ALN or [14C]zoledronate was inhibited by dansylcadaverine, indicating that fluid-phase endocytosis is involved in the initial internalization of bisphosphonate into vesicles. Endosomal acidification then seems to be absolutely required for exit of bisphosphonate from vesicles and entry into the cytosol, because monensin and bafilomycin A1, both inhibitors of endosomal acidification, did not inhibit vesicular uptake of AF-ALN or internalization of [14C]zoledronate but prevented the inhibitory effect of alendronate or zoledronate on Rap1A prenylation. Taken together, these results demonstrate that cellular uptake of bisphosphonate drugs requires fluid-phase endocytosis and is enhanced by Ca2+ ions, whereas transfer from endocytic vesicles into the cytosol requires endosomal acidification.


Drug Design Development and Therapy | 2013

Osteoporosis – a current view of pharmacological prevention and treatment

Subhajit Das; Julie C. Crockett

Postmenopausal osteoporosis is the most common bone disease, associated with low bone mineral density (BMD) and pathological fractures which lead to significant morbidity. It is defined clinically by a BMD of 2.5 standard deviations or more below the young female adult mean (T-score =−2.5). Osteoporosis was a huge global problem both socially and economically – in the UK alone, in 2011 £6 million per day was spent on treatment and social care of the 230,000 osteoporotic fracture patients – and therefore viable preventative and therapeutic approaches are key to managing this problem within the aging population of today. One of the main issues surrounding the potential of osteoporosis management is diagnosing patients at risk before they develop a fracture. We discuss the current and future possibilities for identifying susceptible patients, from fracture risk assessment to shape modeling and in relation to the high heritability of osteoporosis now that a plethora of genes have been associated with low BMD and osteoporotic fracture. This review highlights the current therapeutics in clinical use (including bisphosphonates, anti-RANKL [receptor activator of NF-κB ligand], intermittent low dose parathyroid hormone, and strontium ranelate) and some of those in development (anti-sclerostin antibodies and cathepsin K inhibitors). By highlighting the intimate relationship between the activities of bone forming (osteoblasts) and bone-resorbing (osteoclasts) cells, we include an overview and comparison of the molecular mechanisms exploited in each therapy.


Osteoporosis International | 2011

New knowledge on critical osteoclast formation and activation pathways from study of rare genetic diseases of osteoclasts: focus on the RANK/RANKL axis

Julie C. Crockett; David Mellis; D. I. Scott; Miep H. Helfrich

Functional, biochemical and genetic studies have over the past decade identified many causative genes in the osteoclast diseases osteopetrosis and Pagets disease of bone. Here, we outline all osteoclast diseases and their genetic associations and then focus specifically on those diseases caused by mutations in the critical osteoclast molecule Receptor Activator of Nuclear factor Kappa B (RANK). Both loss and gain-of-function mutations have been found in humans leading to osteopetrosis and high bone turnover phenotypes, respectively. Osteopetrosis-associated RANK mutations are widely distributed over the RANK molecule. It is likely that some negatively affect ligand binding, whereas others preclude appropriate association of RANK with downstream signalling molecules. In the Paget-like disorders, familial expansile osteolysis, early onset Pagets disease and expansile skeletal hyperphosphatasia, heterozygous insertion mutations are found in the RANK signal peptide. These prevent signal peptide cleavage, trapping the protein translated from the mutated allele in the endoplasmic reticulum. Whole animal studies replicate the hyperactive osteoclast phenotype associated with these disorders and present only with heterozygous expression of the mutation, suggesting an as yet unexplained effect of the mutant allele on normal RANK function. We discuss the cell biological studies and animal models that help us to understand the nature of these different RANK defects and describe how careful dissection of these conditions can help understand critical pathways in osteoclast development and function. We highlight areas that require further study, particularly in light of the pharmacological interest in targeting the RANK signalling pathway to treat diseases caused by excessive bone resorption.


Journal of Endocrinology | 2011

The skeleton: a multi-functional complex organ. The role of key signalling pathways in osteoclast differentiation and in bone resorption

David Mellis; Cecile Itzstein; Marie Helfrich; Julie C. Crockett

Osteoclasts are the specialised cells that resorb bone matrix and are important both for the growth and shaping of bones throughout development as well as during the process of bone remodelling that occurs throughout life to maintain a healthy skeleton. Osteoclast formation, function and survival are tightly regulated by a network of signalling pathways, many of which have been identified through the study of rare monogenic diseases, knockout mouse models and animal strains carrying naturally occurring mutations in key molecules. In this review, we describe the processes of osteoclast formation, activation and function and discuss the major transcription factors and signalling pathways (including those that control the cytoskeletal rearrangements) that are important at each stage.


British Journal of Pharmacology | 2009

Zoledronic acid induces formation of a pro-apoptotic ATP analogue and isopentenyl pyrophosphate in osteoclasts in vivo and in MCF-7 cells in vitro

Johanna Räikkönen; Julie C. Crockett; Michael J. Rogers; Hannu Mönkkönen; Seppo Auriola; Jukka Mönkkönen

Background and purpose:  Bisphosphonates (BPs) are highly effective inhibitors of bone resorption. Nitrogen‐containing bisphosphonates (N‐BPs), such as zoledronic acid, induce the formation of a novel ATP analogue (1‐adenosin‐5′‐yl ester 3‐(3‐methylbut‐3‐enyl) ester triphosphoric acid; ApppI), as a consequence of the inhibition of farnesyl pyrophosphate synthase and the accumulation of isopentenyl pyrophosphate (IPP). ApppI induces apoptosis, as do comparable metabolites of non‐nitrogen‐containing bisphosphonates (non‐N‐BPs). In order to further evaluate a pharmacological role for ApppI, we obtained more detailed data on IPP/ApppI formation in vivo and in vitro. Additionally, zoledronic acid‐induced ApppI formation from IPP was compared with the metabolism of clodronate (a non‐N‐BP) to adenosine 5′(β,γ‐dichloromethylene) triphosphate (AppCCl2p).


Journal of Bone and Mineral Research | 2012

RANK-Dependent Autosomal Recessive Osteopetrosis: Characterization of Five New Cases With Novel Mutations

Alessandra Pangrazio; Barbara Cassani; Matteo M Guerrini; Julie C. Crockett; Veronica Marrella; Luca Zammataro; Dario Strina; Ansgar Schulz; Claire Schlack; Uwe Kornak; David Mellis; Angela Duthie; Miep H. Helfrich; Anne Durandy; Despina Moshous; Ashok Vellodi; Robert Chiesa; Paul Veys; Nadia Lo Iacono; Paolo Vezzoni; Alain Fischer; Anna Villa; Cristina Sobacchi

Autosomal recessive osteopetrosis (ARO) is a genetically heterogeneous disorder attributed to reduced bone resorption by osteoclasts. Most human AROs are classified as osteoclast rich, but recently two subsets of osteoclast‐poor ARO have been recognized as caused by defects in either TNFSF11 or TNFRSF11A genes, coding the RANKL and RANK proteins, respectively. The RANKL/RANK axis drives osteoclast differentiation and also plays a role in the immune system. In fact, we have recently reported that mutations in the TNFRSF11A gene lead to osteoclast‐poor osteopetrosis associated with hypogammaglobulinemia. Here we present the characterization of five additional unpublished patients from four unrelated families in which we found five novel mutations in the TNFRSF11A gene, including two missense and two nonsense mutations and a single‐nucleotide insertion. Immunological investigation in three of them showed that the previously described defect in the B cell compartment was present only in some patients and that its severity seemed to increase with age and the progression of the disease. HSCT performed in all five patients almost completely cured the disease even when carried out in late infancy. Hypercalcemia was the most important posttransplant complication. Overall, our results further underline the heterogeneity of human ARO also deriving from the interplay between bone and the immune system, and highlight the prognostic and therapeutic implications of the molecular diagnosis.


Journal of Bone and Mineral Research | 2011

Signal peptide mutations in RANK prevent downstream activation of NF-κB

Julie C. Crockett; David Mellis; Kathleen I. J. Shennan; Angela Duthie; John Greenhorn; Debbie Wilkinson; Stuart H. Ralston; Miep H. Helfrich; Michael J. Rogers

Familial expansile osteolysis and related disorders are caused by heterozygous tandem duplication mutations in the signal peptide region of the gene encoding receptor activator of NF‐κB (RANK), a receptor critical for osteoclast formation and function. Previous studies have shown that overexpression of these mutant proteins causes constitutive activation of NF‐κB signaling in vitro, and it has been assumed that this accounts for the focal osteolytic lesions that are seen in vivo. We show here that constitutive activation of NF‐κB occurred in HEK293 cells overexpressing wild‐type or mutant RANK but not in stably transfected cell lines expressing low levels of each RANK gene. Importantly, only cells expressing wild‐type RANK demonstrated ligand‐dependent activation of NF‐κB. When overexpressed, mutant RANK did not localize to the plasma membrane but localized to extensive areas of organized smooth endoplasmic reticulum, whereas, as expected, wild‐type RANK was detected at the plasma membrane and in the Golgi apparatus. This intracellular accumulation of the mutant proteins is probably the result of lack of signal peptide cleavage because, using two in vitro translation systems, we demonstrate that the mutations in RANK prevent cleavage of the signal peptide. In conclusion, signal peptide mutations lead to accumulation of RANK in the endoplasmic reticulum and prevent direct activation by RANK ligand. These results strongly suggest that the increased osteoclast formation/activity caused by these mutations cannot be explained by studying the homozygous phenotype alone but requires further detailed investigation of the heterozygous expression of the mutant RANK proteins.

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Michael J. Rogers

Garvan Institute of Medical Research

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Susan Clark

University of Aberdeen

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