Objectives. Extracellular inorganic pyrophosphate (ePPi) inhibits certain forms of pathological m... more Objectives. Extracellular inorganic pyrophosphate (ePPi) inhibits certain forms of pathological mineralization while promoting others. Three molecules involved in ePPi regulation are important candidates for the development of calcium pyrophosphate dihydrate chondrocalcinosis (CPPD CC). These include ANKH, ectonucleotide pyrophosphatase (ENPP1) and TNAP. We have previously showed that genetic variation in ANKH is a cause of autosomal dominant familial CC and also some sporadic cases of CPPD CC. We now investigate the possible role of ENPP1 and TNAP in CPPD CC. Methods. Exons, untranslated regions (UTR) and exon-intron boundaries of ENPP1 and TNAP were sequenced using ABI Big Dye chemistry on automated sequencers. Sixteen variants were identified (3 in ENPP1 and 13 in TNAP) and were subsequently genotyped in 128 sporadic Caucasian CPPD CC patients and 600 healthy controls using a combination of polymerase chain reaction/restriction fragment-length polymorphism analysis or using Taqman. Allele and genotype frequencies were compared between cases and controls using the 2 test. Linkage disequilibrium, haplotype and the single nucleotide polymorphism-specific analyses were also performed. This study had 80% power to detect an odds ratio of 2.2 or more at these loci. Results. No difference was observed in the allele or genotype frequencies between patients and controls at either ENPP1 or TNAP. Conclusions. Polymorphisms of ENPP1 and TNAP are not major determinants of susceptibility to CC in the population studied. Further studies of the aetiology of sporadic CPPD CC are required to determine its causes.
In addition to reducing fracture risk, zoledronic acid has been found in some studies to decrease... more In addition to reducing fracture risk, zoledronic acid has been found in some studies to decrease mortality in humans and extend lifespan and healthspan in animals. Because senescent cells accumulate with aging and contribute to multiple co-morbidities, the non-skeletal actions of zoledronic acid could be due to senolytic (killing of senescent cells) or senomorphic (inhibition of the secretion of the senescence-associated secretory phenotype [SASP]) actions. To test this, we first performed in vitro senescence assays using human lung fibroblasts and DNA repair-deficient mouse embryonic fibroblasts, which demonstrated that zoledronic acid killed senescent cells with minimal effects on non-senescent cells. Next, in aged mice treated with zoledronic acid or vehicle for 8 weeks, zoledronic acid significantly reduced circulating SASP factors, including CCL7, IL-1β, TNFRSF1A, and TGFβ1 and improved grip strength. Analysis of publicly available RNAseq data from CD115+ (CSF1R/c-fms+) pre-osteoclastic cells isolated from mice treated with zoledronic acid demonstrated a significant downregulation of senescence/SASP genes (SenMayo). To establish that these cells are potential senolytic/senomorphic targets of zoledronic acid, we used single cell proteomic analysis (cytometry by time of flight [CyTOF]) and demonstrated www.aging-us.com
and bone disease. Later he held a Lectureship in the Gardiner Institute in Glasgow Western Infirm... more and bone disease. Later he held a Lectureship in the Gardiner Institute in Glasgow Western Infirmary where I (WGR) joined him as a PhD student in 1963 to carry out research on the physical chemical aspects of stone-formation. Exactly a year later, Chris was appointed as Director of the new MRC Mineral Metabolism Research Unit (later renamed the MRC Mineral Metabolism Unit) in the General Infirmary at Leeds and I was fortunate to be invited to accompany him in order to complete the research for my thesis. (The dropping of the word "Research" in the title of the Unit caused no little amusement among Chris's competitors in the calcium world but the purpose of this was to alleviate any patient fears that they might be used as guinea pigs rather than to suggest that no research would be carried out in the Unit!) The new Unit took the place of the pre-existing Research Unit for Metabolism Disturbances in Surgery (also supported by the MRC) when its Director (Professor Leslie Pyrah, a pioneering urologist famous for his research into primary hyperparathyroidism and renal stone disease) retired. One of us (RGGR) was already studying for a PhD in Leslie Pyrah's Unit, under the supervision of the late Albert Hodgkinson, on the role of inhibitors of crystallisation, particularly pyrophosphate, in the prevention of stone-formation. So, both of us were involved from different sources in the inception of the embryonic Mineral Metabolism Unit under its new Director. As Director of the MMU, Chris soon earned an international reputation for his research into disorders of calcium metabolism and bone disease, particularly osteoporosis.
Anterior cruciate ligament (ACL) rupture increases the risk for osteoarthritis (OA). This study a... more Anterior cruciate ligament (ACL) rupture increases the risk for osteoarthritis (OA). This study aims to clarify temporal alterations in subchondral bone (SCB) and articular cartilage in a rabbit model with surgical ACL transection (ACLT). Operated (ACLT) and contralateral (C-L) knees were harvested two (n=8) and eight (n=6) weeks after ACLT, surgery together with collection of age-matched control (CNTRL, n=8) knees. Each knee was divided into lateral and medial condyles and plateaus, groove and patella. Bone morphology was quantified using micro-computed tomography. Thickness and fixed charged density (FCD) of the cartilage were measured with optical coherence tomography and digital densitometry, respectively. Trabeculae in ACLT knees were thinner compared to C-L in the lateral plateau (-6.7%;p=0.007) and groove (-10.9%;p=0.015) two weeks after surgery. At eight weeks, thinner trabeculae compared to C-L were observed at all locations. Trabecular bone volume fraction was decreased in ACLT compared to CNTRL at all locations except for the patella. Subchondral plate was thinner than C-L in the lateral plateau (-26.2%;p=0.022), groove (-19.8%;p=0.005) and patella (-19.5%; p=0.001). Two weeks after surgery, FCD was reduced at the lateral plateau, the medial condyles, the groove, and the patella in ACLT compared to CNTRL. FCD was lower in the ACLT compared to C-L at all locations except for the lateral plateau. Interestingly, eight weeks after surgery, the FCD was increased in the medial plateau of C-L compared to CNTRL group knees. FCD loss in ACLT was progressive in the condyles, but the initial FCD loss was compensated for in the groove and patella. Also, the cartilage was thicker (50.5%;p=0.007) in the lateral plateau of ACLT knees eight weeks after surgery compared to CNTRL. Summarizing, bone loss and cartilage degeneration occurred in a tissue-and site-specific manner in post-ACLT knees and bone loss spread progressively while some compositional changes of cartilage were recovered.
Inorganic pyrophosphate has long been known as a by-product of many intracellular biosynthetic re... more Inorganic pyrophosphate has long been known as a by-product of many intracellular biosynthetic reactions, and was first identified as a key endogenous inhibitor of biomineralisation in the 1960s. The major source of pyrophosphate appears to be extracellular ATP, which is released from cells in a controlled manner. Once released, ATP can be rapidly hydrolysed by ecto-nucleotide pyrophosphatase/phosphodiesterases to produce pyrophosphate. The main action of pyrophosphate is to directly inhibit hydroxyapatite formation thereby acting as a physiological 'water-softener'. Evidence suggests pyrophosphate may also act as a signalling molecule to influence gene expression and regulate its own production and breakdown. This review will summarise our current understanding of pyrophosphate metabolism and how it regulates bone mineralisation and prevents harmful soft tissue calcification.
We have shown previously that the concentration of orthophosphate (P,) in human erythrocytes and ... more We have shown previously that the concentration of orthophosphate (P,) in human erythrocytes and skeletal muscle is regulated in response to changes in the extracellular Pi concentration (Bevington et al., 1986). This is in marked contrast to earlier reports that P, simply distributes passively between mammalian cells and extracellular fluid (Deuticke, 1967; Tenenhouse & Scriver, 1975). To compare the extent of regulation of the cellular PI concentration between cell types or in a given cell type under a series of different conditions, some convenient method is needed to quantify the regulation. Wc therefore propose the following phosphate regulation index, p . If the relationship between the extracellular P, concentration (C, in mmol/l) and the cellular P, concentration (C,) is approximately linear, so that Cz = a + bC,, p is taken to be the ratio of the steady-state cellular P, concentration when C , = 0 to the cellular Pi concentration when C , = 1 mM, so that p = a / ( a + 6 ) . The value of 1 mM is chosen for the second extracellular P, concentration as this is approximately the concentration in normal human extracellular fluid. This index has some useful properties. In a cell which can regulate its P, concentration perfectly so that C', is constant as C, varies, p = 1; whereas in a cell in which P, is passively distributed so that C, is directly proportional to C,, p = 0. A furthcr advantage is that p is the ratio of two cellular P, concentrations, so that it is independent of the units in which the concentrations are expressed (e.g. mmol/l of cell water, or pmol/mg of protein). In Table 1 we summarize 10 published studies of the relationship betwecn C, and C, from which values of p can be derived. In seven of the 10 studies the relationship deviates markedly from that expected if P, distributes passively (because p 0.4). In -human erythrocytes, p seems to depend on the precise conditions under which it is measured.
IntroductionPaget’s disease of bone (PDB) is characterised by increased and disorganised bone rem... more IntroductionPaget’s disease of bone (PDB) is characterised by increased and disorganised bone remodelling affecting one or more skeletal sites. Complications include bone pain, deformity, deafness and pathological fractures. Mutations in sequestosome-1 (SQSTM1) are strongly associated with the development of PDB. Bisphosphonate therapy can improve bone pain in PDB, but there is no evidence that treatment alters the natural history of PDB or prevents complications. The Zoledronate in the Prevention of Paget’s disease trial (ZiPP) will determine if prophylactic therapy with the bisphosphonate zoledronic acid (ZA) can delay or prevent the development of PDB in people who carrySQSTM1mutations.Methods and analysisPeople with a family history of PDB aged >30 years who test positive forSQSTM1mutations are eligible to take part. At the baseline visit, participants will be screened for the presence of bone lesions by radionuclide bone scan. Biochemical markers of bone turnover will be mea...
Abstract The year 2019 marks 50 years since the first publications on the biological effects of b... more Abstract The year 2019 marks 50 years since the first publications on the biological effects of bisphosphonates (BPs). These agents have served for the past several decades as the pharmacological cornerstone for the treatment of skeletal disorders such as Paget’s disease of bone, osteoporosis and cancers metastatic to bone. The early discovery and clinical development of BPs has been reviewed elsewhere. Abundant preclinical, translational and clinical research with BPs has led to a wealth of data that now enable us to rationally prescribe these drugs to the right patients using tailored dosing regimens to provide an optimal balance between efficacy and side effects. Better insight into the precise effects of BPs on various bone cell populations has resulted in continued efforts to develop new BPs for the treatment of metabolic bone diseases, while non-skeletal-related indications for these drugs have been more recently explored. In addition, BPs are currently under investigation as agents for the targeting of other drugs, such as antibiotics, to bone tissue. This chapter provides an overview of our current knowledge on the (pre-) clinical and translational pharmacology of BPs, and illustrates how this knowledge has been used both for the development of new compounds and for the treatment of patients.
E. Michael Lewiecki,* John P. Bilezikian, Andrew J. Laster, Paul D. Miller, Robert R. Recker, R. ... more E. Michael Lewiecki,* John P. Bilezikian, Andrew J. Laster, Paul D. Miller, Robert R. Recker, R. Graham G. Russell, and Michael P. Whyte New Mexico Clinical Research & Osteoporosis Center, Albuquerque, NM, USA; Columbia University College of Physicians and Surgeons, NYC, NY, USA; Arthritis and Osteoporosis Consultants of the Carolinas, Charlotte, NC, USA; Colorado Center for Bone Research, Lakewood, CO, USA; Creighton University School of Medicine, Omaha, NE, USA; The Botnar Research Centre, University of Oxford, Oxford, UK; and Washington University School of Medicine, St. Louis, MO, USA
We studied the effects of bilateral nephrectomy on bone metabolism in 27 patients on maintenance ... more We studied the effects of bilateral nephrectomy on bone metabolism in 27 patients on maintenance hemodialysis. After nephrectomy plasma alkaline phosphatase fell rapidly in 10 patients whose preoperative plasma levels had been higher than normal. This fall was associated with a transient decrease in osteoblast counts of iliac-bone biopsies. A fall in plasma phosphate and a rise in plasma immunoreactive calcitonin also occurred, but calcium and immunoreactive parathyroid hormone levels did not change. Alkaline phosphatase levels remained unchanged in a control group of 17 patients on dialysis who had undergone an operation other than nephrectomy. In 26 nonsurgical patients on dialysis, immunoreactive calcitonin was inversely related to osteoblast counts. Rises in immunoreactive calcitonin may be partly responsible for the transient decreases in bone turnover after bilateral nephrectomy. Low levels of endogenous calcitonin may allow an increase in bone turnover in chronic renal failure.
for the two components suggests that there is as yet no reason to postulate separate P, transport... more for the two components suggests that there is as yet no reason to postulate separate P, transporters for the labelling of cellular Pi and OP in these cells. Nevertheless, we discuss elsewhere factors which affect the proportions of j2P taken up into cellular Pi and OP (Kemp et al., 1989).
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, Jan 29, 2016
The activity of the epigenetic writers DNA methyltransferases (Dnmts) after olfactory reward cond... more The activity of the epigenetic writers DNA methyltransferases (Dnmts) after olfactory reward conditioning is important for both stimulus-specific long-term memory (LTM) formation and extinction. It, however, remains unknown which components of memory formation Dnmts regulate (e.g., associative vs. non-associative) and in what context (e.g., varying training conditions). Here, we address these aspects in order to clarify the role of Dnmt-mediated DNA methylation in memory formation. We used a pharmacological Dnmt inhibitor and classical appetitive conditioning in the honeybee Apis mellifera, a well characterized model for classical conditioning. We quantified the effect of DNA methylation on naïve odor and sugar responses, and on responses following olfactory reward conditioning. We show that (1) Dnmts do not influence naïve odor or sugar responses, (2) Dnmts do not affect the learning of new stimuli, but (3) Dnmts influence odor-coding, i.e., 'correct' (stimulus-specific) LTM formation. Particularly, Dnmts reduce memory specificity when experience is low (one-trial training), and increase memory specificity when experience is high (multiple-trial training), generating an ecologically more useful response to learning. (4) In reversal learning conditions, Dnmts are involved in regulating both excitatory (re-acquisition) and inhibitory (forgetting) processes.
Drugs for the treatment of metabolic bone diseases Musculoskeletal conditions comprise more than ... more Drugs for the treatment of metabolic bone diseases Musculoskeletal conditions comprise more than 150 diagnoses that affect the locomotor system-that is, muscles, bones, joints, and associated tissues such as tendons and ligaments. 1 Musculoskeletal
Objectives. Extracellular inorganic pyrophosphate (ePPi) inhibits certain forms of pathological m... more Objectives. Extracellular inorganic pyrophosphate (ePPi) inhibits certain forms of pathological mineralization while promoting others. Three molecules involved in ePPi regulation are important candidates for the development of calcium pyrophosphate dihydrate chondrocalcinosis (CPPD CC). These include ANKH, ectonucleotide pyrophosphatase (ENPP1) and TNAP. We have previously showed that genetic variation in ANKH is a cause of autosomal dominant familial CC and also some sporadic cases of CPPD CC. We now investigate the possible role of ENPP1 and TNAP in CPPD CC. Methods. Exons, untranslated regions (UTR) and exon-intron boundaries of ENPP1 and TNAP were sequenced using ABI Big Dye chemistry on automated sequencers. Sixteen variants were identified (3 in ENPP1 and 13 in TNAP) and were subsequently genotyped in 128 sporadic Caucasian CPPD CC patients and 600 healthy controls using a combination of polymerase chain reaction/restriction fragment-length polymorphism analysis or using Taqman. Allele and genotype frequencies were compared between cases and controls using the 2 test. Linkage disequilibrium, haplotype and the single nucleotide polymorphism-specific analyses were also performed. This study had 80% power to detect an odds ratio of 2.2 or more at these loci. Results. No difference was observed in the allele or genotype frequencies between patients and controls at either ENPP1 or TNAP. Conclusions. Polymorphisms of ENPP1 and TNAP are not major determinants of susceptibility to CC in the population studied. Further studies of the aetiology of sporadic CPPD CC are required to determine its causes.
In addition to reducing fracture risk, zoledronic acid has been found in some studies to decrease... more In addition to reducing fracture risk, zoledronic acid has been found in some studies to decrease mortality in humans and extend lifespan and healthspan in animals. Because senescent cells accumulate with aging and contribute to multiple co-morbidities, the non-skeletal actions of zoledronic acid could be due to senolytic (killing of senescent cells) or senomorphic (inhibition of the secretion of the senescence-associated secretory phenotype [SASP]) actions. To test this, we first performed in vitro senescence assays using human lung fibroblasts and DNA repair-deficient mouse embryonic fibroblasts, which demonstrated that zoledronic acid killed senescent cells with minimal effects on non-senescent cells. Next, in aged mice treated with zoledronic acid or vehicle for 8 weeks, zoledronic acid significantly reduced circulating SASP factors, including CCL7, IL-1β, TNFRSF1A, and TGFβ1 and improved grip strength. Analysis of publicly available RNAseq data from CD115+ (CSF1R/c-fms+) pre-osteoclastic cells isolated from mice treated with zoledronic acid demonstrated a significant downregulation of senescence/SASP genes (SenMayo). To establish that these cells are potential senolytic/senomorphic targets of zoledronic acid, we used single cell proteomic analysis (cytometry by time of flight [CyTOF]) and demonstrated www.aging-us.com
and bone disease. Later he held a Lectureship in the Gardiner Institute in Glasgow Western Infirm... more and bone disease. Later he held a Lectureship in the Gardiner Institute in Glasgow Western Infirmary where I (WGR) joined him as a PhD student in 1963 to carry out research on the physical chemical aspects of stone-formation. Exactly a year later, Chris was appointed as Director of the new MRC Mineral Metabolism Research Unit (later renamed the MRC Mineral Metabolism Unit) in the General Infirmary at Leeds and I was fortunate to be invited to accompany him in order to complete the research for my thesis. (The dropping of the word "Research" in the title of the Unit caused no little amusement among Chris's competitors in the calcium world but the purpose of this was to alleviate any patient fears that they might be used as guinea pigs rather than to suggest that no research would be carried out in the Unit!) The new Unit took the place of the pre-existing Research Unit for Metabolism Disturbances in Surgery (also supported by the MRC) when its Director (Professor Leslie Pyrah, a pioneering urologist famous for his research into primary hyperparathyroidism and renal stone disease) retired. One of us (RGGR) was already studying for a PhD in Leslie Pyrah's Unit, under the supervision of the late Albert Hodgkinson, on the role of inhibitors of crystallisation, particularly pyrophosphate, in the prevention of stone-formation. So, both of us were involved from different sources in the inception of the embryonic Mineral Metabolism Unit under its new Director. As Director of the MMU, Chris soon earned an international reputation for his research into disorders of calcium metabolism and bone disease, particularly osteoporosis.
Anterior cruciate ligament (ACL) rupture increases the risk for osteoarthritis (OA). This study a... more Anterior cruciate ligament (ACL) rupture increases the risk for osteoarthritis (OA). This study aims to clarify temporal alterations in subchondral bone (SCB) and articular cartilage in a rabbit model with surgical ACL transection (ACLT). Operated (ACLT) and contralateral (C-L) knees were harvested two (n=8) and eight (n=6) weeks after ACLT, surgery together with collection of age-matched control (CNTRL, n=8) knees. Each knee was divided into lateral and medial condyles and plateaus, groove and patella. Bone morphology was quantified using micro-computed tomography. Thickness and fixed charged density (FCD) of the cartilage were measured with optical coherence tomography and digital densitometry, respectively. Trabeculae in ACLT knees were thinner compared to C-L in the lateral plateau (-6.7%;p=0.007) and groove (-10.9%;p=0.015) two weeks after surgery. At eight weeks, thinner trabeculae compared to C-L were observed at all locations. Trabecular bone volume fraction was decreased in ACLT compared to CNTRL at all locations except for the patella. Subchondral plate was thinner than C-L in the lateral plateau (-26.2%;p=0.022), groove (-19.8%;p=0.005) and patella (-19.5%; p=0.001). Two weeks after surgery, FCD was reduced at the lateral plateau, the medial condyles, the groove, and the patella in ACLT compared to CNTRL. FCD was lower in the ACLT compared to C-L at all locations except for the lateral plateau. Interestingly, eight weeks after surgery, the FCD was increased in the medial plateau of C-L compared to CNTRL group knees. FCD loss in ACLT was progressive in the condyles, but the initial FCD loss was compensated for in the groove and patella. Also, the cartilage was thicker (50.5%;p=0.007) in the lateral plateau of ACLT knees eight weeks after surgery compared to CNTRL. Summarizing, bone loss and cartilage degeneration occurred in a tissue-and site-specific manner in post-ACLT knees and bone loss spread progressively while some compositional changes of cartilage were recovered.
Inorganic pyrophosphate has long been known as a by-product of many intracellular biosynthetic re... more Inorganic pyrophosphate has long been known as a by-product of many intracellular biosynthetic reactions, and was first identified as a key endogenous inhibitor of biomineralisation in the 1960s. The major source of pyrophosphate appears to be extracellular ATP, which is released from cells in a controlled manner. Once released, ATP can be rapidly hydrolysed by ecto-nucleotide pyrophosphatase/phosphodiesterases to produce pyrophosphate. The main action of pyrophosphate is to directly inhibit hydroxyapatite formation thereby acting as a physiological 'water-softener'. Evidence suggests pyrophosphate may also act as a signalling molecule to influence gene expression and regulate its own production and breakdown. This review will summarise our current understanding of pyrophosphate metabolism and how it regulates bone mineralisation and prevents harmful soft tissue calcification.
We have shown previously that the concentration of orthophosphate (P,) in human erythrocytes and ... more We have shown previously that the concentration of orthophosphate (P,) in human erythrocytes and skeletal muscle is regulated in response to changes in the extracellular Pi concentration (Bevington et al., 1986). This is in marked contrast to earlier reports that P, simply distributes passively between mammalian cells and extracellular fluid (Deuticke, 1967; Tenenhouse & Scriver, 1975). To compare the extent of regulation of the cellular PI concentration between cell types or in a given cell type under a series of different conditions, some convenient method is needed to quantify the regulation. Wc therefore propose the following phosphate regulation index, p . If the relationship between the extracellular P, concentration (C, in mmol/l) and the cellular P, concentration (C,) is approximately linear, so that Cz = a + bC,, p is taken to be the ratio of the steady-state cellular P, concentration when C , = 0 to the cellular Pi concentration when C , = 1 mM, so that p = a / ( a + 6 ) . The value of 1 mM is chosen for the second extracellular P, concentration as this is approximately the concentration in normal human extracellular fluid. This index has some useful properties. In a cell which can regulate its P, concentration perfectly so that C', is constant as C, varies, p = 1; whereas in a cell in which P, is passively distributed so that C, is directly proportional to C,, p = 0. A furthcr advantage is that p is the ratio of two cellular P, concentrations, so that it is independent of the units in which the concentrations are expressed (e.g. mmol/l of cell water, or pmol/mg of protein). In Table 1 we summarize 10 published studies of the relationship betwecn C, and C, from which values of p can be derived. In seven of the 10 studies the relationship deviates markedly from that expected if P, distributes passively (because p 0.4). In -human erythrocytes, p seems to depend on the precise conditions under which it is measured.
IntroductionPaget’s disease of bone (PDB) is characterised by increased and disorganised bone rem... more IntroductionPaget’s disease of bone (PDB) is characterised by increased and disorganised bone remodelling affecting one or more skeletal sites. Complications include bone pain, deformity, deafness and pathological fractures. Mutations in sequestosome-1 (SQSTM1) are strongly associated with the development of PDB. Bisphosphonate therapy can improve bone pain in PDB, but there is no evidence that treatment alters the natural history of PDB or prevents complications. The Zoledronate in the Prevention of Paget’s disease trial (ZiPP) will determine if prophylactic therapy with the bisphosphonate zoledronic acid (ZA) can delay or prevent the development of PDB in people who carrySQSTM1mutations.Methods and analysisPeople with a family history of PDB aged >30 years who test positive forSQSTM1mutations are eligible to take part. At the baseline visit, participants will be screened for the presence of bone lesions by radionuclide bone scan. Biochemical markers of bone turnover will be mea...
Abstract The year 2019 marks 50 years since the first publications on the biological effects of b... more Abstract The year 2019 marks 50 years since the first publications on the biological effects of bisphosphonates (BPs). These agents have served for the past several decades as the pharmacological cornerstone for the treatment of skeletal disorders such as Paget’s disease of bone, osteoporosis and cancers metastatic to bone. The early discovery and clinical development of BPs has been reviewed elsewhere. Abundant preclinical, translational and clinical research with BPs has led to a wealth of data that now enable us to rationally prescribe these drugs to the right patients using tailored dosing regimens to provide an optimal balance between efficacy and side effects. Better insight into the precise effects of BPs on various bone cell populations has resulted in continued efforts to develop new BPs for the treatment of metabolic bone diseases, while non-skeletal-related indications for these drugs have been more recently explored. In addition, BPs are currently under investigation as agents for the targeting of other drugs, such as antibiotics, to bone tissue. This chapter provides an overview of our current knowledge on the (pre-) clinical and translational pharmacology of BPs, and illustrates how this knowledge has been used both for the development of new compounds and for the treatment of patients.
E. Michael Lewiecki,* John P. Bilezikian, Andrew J. Laster, Paul D. Miller, Robert R. Recker, R. ... more E. Michael Lewiecki,* John P. Bilezikian, Andrew J. Laster, Paul D. Miller, Robert R. Recker, R. Graham G. Russell, and Michael P. Whyte New Mexico Clinical Research & Osteoporosis Center, Albuquerque, NM, USA; Columbia University College of Physicians and Surgeons, NYC, NY, USA; Arthritis and Osteoporosis Consultants of the Carolinas, Charlotte, NC, USA; Colorado Center for Bone Research, Lakewood, CO, USA; Creighton University School of Medicine, Omaha, NE, USA; The Botnar Research Centre, University of Oxford, Oxford, UK; and Washington University School of Medicine, St. Louis, MO, USA
We studied the effects of bilateral nephrectomy on bone metabolism in 27 patients on maintenance ... more We studied the effects of bilateral nephrectomy on bone metabolism in 27 patients on maintenance hemodialysis. After nephrectomy plasma alkaline phosphatase fell rapidly in 10 patients whose preoperative plasma levels had been higher than normal. This fall was associated with a transient decrease in osteoblast counts of iliac-bone biopsies. A fall in plasma phosphate and a rise in plasma immunoreactive calcitonin also occurred, but calcium and immunoreactive parathyroid hormone levels did not change. Alkaline phosphatase levels remained unchanged in a control group of 17 patients on dialysis who had undergone an operation other than nephrectomy. In 26 nonsurgical patients on dialysis, immunoreactive calcitonin was inversely related to osteoblast counts. Rises in immunoreactive calcitonin may be partly responsible for the transient decreases in bone turnover after bilateral nephrectomy. Low levels of endogenous calcitonin may allow an increase in bone turnover in chronic renal failure.
for the two components suggests that there is as yet no reason to postulate separate P, transport... more for the two components suggests that there is as yet no reason to postulate separate P, transporters for the labelling of cellular Pi and OP in these cells. Nevertheless, we discuss elsewhere factors which affect the proportions of j2P taken up into cellular Pi and OP (Kemp et al., 1989).
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, Jan 29, 2016
The activity of the epigenetic writers DNA methyltransferases (Dnmts) after olfactory reward cond... more The activity of the epigenetic writers DNA methyltransferases (Dnmts) after olfactory reward conditioning is important for both stimulus-specific long-term memory (LTM) formation and extinction. It, however, remains unknown which components of memory formation Dnmts regulate (e.g., associative vs. non-associative) and in what context (e.g., varying training conditions). Here, we address these aspects in order to clarify the role of Dnmt-mediated DNA methylation in memory formation. We used a pharmacological Dnmt inhibitor and classical appetitive conditioning in the honeybee Apis mellifera, a well characterized model for classical conditioning. We quantified the effect of DNA methylation on naïve odor and sugar responses, and on responses following olfactory reward conditioning. We show that (1) Dnmts do not influence naïve odor or sugar responses, (2) Dnmts do not affect the learning of new stimuli, but (3) Dnmts influence odor-coding, i.e., 'correct' (stimulus-specific) LTM formation. Particularly, Dnmts reduce memory specificity when experience is low (one-trial training), and increase memory specificity when experience is high (multiple-trial training), generating an ecologically more useful response to learning. (4) In reversal learning conditions, Dnmts are involved in regulating both excitatory (re-acquisition) and inhibitory (forgetting) processes.
Drugs for the treatment of metabolic bone diseases Musculoskeletal conditions comprise more than ... more Drugs for the treatment of metabolic bone diseases Musculoskeletal conditions comprise more than 150 diagnoses that affect the locomotor system-that is, muscles, bones, joints, and associated tissues such as tendons and ligaments. 1 Musculoskeletal
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