Jürg Andreas Gasser

Hypercalciuria is a common feature during metabolic acidosis and associates to nephrolithiasis and nephrocalcinosis. The mechanisms sensing acidosis and inducing increased urinary calcium excretion are still unknown. Here we tested whether mice deficient for proton-activated Ovarian cancer G-protein coupled receptor 1 (OGR1 or Gpr68) have reduced u...

This chapter provides information for the in vivo use of peripheral quantitative computed tomography in rats and mice to determine bone density and cortical geometric data, including suggestions for study design, instrument setting, and data interpretation. This update also provides guidance for the use of pQCT to extract muscle and fat cross-secti...

This chapter is divided into three subsections: The bone biology part will provide some insight into the matrix composition as well as the origin and basic function attributed to the cellular components, the osteoblasts osteocytes and osteoclasts. In the second section, the interplay between these matrix components and the cells will be discussed i...

Six month old female rats were either pair fed an isocaloric low protein (2.5 casein, LP) or a normal protein diet (15% casein, NP) for 2 weeks. The rats continued on their respective diet while being treated with 5 or 40μ g/kg recombinant human PTH amino-terminal fragment 1-34 (PTH(1-34)) daily, or with vehicle for 4 weeks. At the end of this peri...

Chronic metabolic acidosis (CMA) might result in a decrease in bone mass in vivo based on its reported in vitro inhibition of bone mineralization, bone formation or stimulation of bone resorption, but such data, in the absence of other disorders, have not been reported. CMA also results in negative nitrogen balance which might decrease skeletal mus...

The efficacy of 3 years' annual intravenous administration of zoledronic acid (ZOL) in reducing vertebral and non-vertebral fractures in postmenopausal osteoporosis has been shown by the HORIZON pivotal fracture trial. Histomorphometric analysis of transiliac bone biopsies from the HORIZON participants revealed significantly improved trabecular arc...

Once-yearly administration of intravenous zoledronic acid for 3 years in humans affects the kinetics of matrix filling in by mineral, independent of bone turnover. Introduction Yearly 5-mg infusions of zoledronic acid (ZOL) for 3 years have shown pronounced antifracture efficacy. The purpose of the present study was to test whether ZOL affects the...

Abstract In fetal autopsies coronal clefts - a radiolucent band running through at least one vertebral body, visualized in the lateral spinal radiograph and discussed as a physiological variation of the fetal vertebral ossification pattern - are often found in fetuses with trisomies. Published studies are missing concerning the question whether thi...

This chapter provides information for the use of peripheral quantitative computed tomography in small animals, including suggestions for study design, instrument setting, and data interpretation.

Clinical data suggest concomitant therapy with bisphosphonates and parathyroid hormone (PTH) may blunt the anabolic effect of PTH; rodent models suggest that infrequently administered bisphosphonates may interact differently. To evaluate the effects of combination therapy with an intravenous infusion of zoledronic acid 5 mg and daily subcutaneous r...

Zoledronic acid (ZOL), a third-generation aminobisphosphonate, showed pronounced antifracture efficacy in a phase III clinical trial [Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT)] when administered yearly (5-mg infusions of ZOL), producing significant reductions in morphometric vertebra...

Background: Imatinib (IMA) is highly effective in the therapy of chronic myeloid leukemia (CML) by inhibiting the constitutively active tyrosine kinase (TK) domain of the BCR-ABL fusion gene via competition for the ATP binding. However, IMA exhibits off-target effects and also binds to TKs like c-Kit, PDGF-R and c-FMS. As these TKs are ative in ost...

The current study employs the immobilization (IM) rat model to induce osteopenia, parathyroid hormone (PTH) as the anabolic agent to restore bone mass, and 17 beta-estradiol, calcitonin, or risedronate as the maintenance agents to answer the following questions: How much cancellous bone loss occurs when PTH is withdrawn? Which antiresorptive or ant...

The bone matrix is composed mostly of collagen, but the initial and continuous presence of fibronectin was found to be crucial for collagen matrix integrity in vitro. It has been assumed that osteoblasts produce the fibronectin required for bone matrix formation. Using transgenic mice, we conditionally deleted fibronectin in the osteoblasts and in...

Chronic inflammation is a major risk factor for systemic bone loss leading to osteoporotic fracture and substantial morbidity and mortality. Inflammatory cytokines, particularly tumour necrosis factor (TNF) and interleukin-1 (IL1), are thought to play a key role in the pathogenesis of inflammation-induced bone loss, but their exact roles are yet to...

Jüngste klinische Untersuchungen deuten darauf hin, daß es als Folge einer intestinalen Blasensubstitution zu Osteopathien kommen kann. Vollkommen unklar ist der zugrunde liegende Pathomechanismus. Als Ursache eventueller Störungen des Knochenstoffwechsels nach einer transintestinalen Harnableitung muß neben der chronisch metabolischen Azidose der...

The goal of this study was to assess the effect of the addition of TGFbeta(3), alone or in combination with loading, on the survival of osteocytes in 3D human explant cancellous bone during long-term culture in an ex vivo loading bioreactor. Human cancellous bone explants were cultured for up to 14 days with or without TGFbeta(3) (15 ng ml(-1)) and...

Objectives: Chronic myeloid leukemia (CML) is effectively treated by Imatinib (IM) via inhibition of the BCR-ABL tyrosine kinase. However, also related tyrosine kinases like abl, c-Kit, PDGF-R, and c-FMS are blocked by IM. As shown in adult humans and mice, abl-controlled protein folding as part of the endoplasmatic stress response in heart myoblas...

In longitudinal studies, three-dimensional (3D) bone images are acquired at sequential time points essentially resulting in four-dimensional (4D) data for an individual. Based on the 4D data, we propose to calculate temporal trends and project these trends to estimate future bone architecture. Multiple consecutive deformation fields, calculated wit...

Biological substitutes for autologous bone flaps could be generated by combining flap pre-fabrication and bone tissue engineering concepts. Here, we investigated the pattern of neotissue formation within large pre-fabricated engineered bone flaps in rabbits. Bone marrow stromal cells from 12 New Zealand White rabbits were expanded and uniformly see...

Delayed union and nonunion are common complications associated with tibial fractures, particularly in the distal tibia. Existing mouse tibial fracture models are typically closed and middiaphyseal, and thus poorly recapitulate the prevailing conditions following surgery on a human open distal tibial fracture. This report describes our development o...

In longitudinal studies, three-dimensional (3D) bone images are acquired at sequential time points essentially resulting in four-dimensional (4D) data for an individual. Based on the 4D data, we propose to calculate temporal trends and project these trends to estimate future bone architecture. Multiple consecutive deformation fields, calculated wit...

Current bisphosphonate therapies effectively prevent bone loss in postmenopausal women. We studied the effect of a single intravenous dose of ZOL in ovariectomized rats. Protection from bone loss was dose dependent, lasting for up to 32 weeks, supporting the rationale for an annual intravenous dosing regimen of ZOL for treatment of postmenopausal o...

Bisphosphonates are antiresorptive drugs commonly used to treat osteoporosis. It is not clear, however, what the influence of the time point of treatment is. Recently developed in vivo micro-computed tomographic (CT) scanners offer the possibility to study such effects on bone microstructure in rats. The aim of this study was to determine the influ...

In a substudy of the HORIZON pivotal fracture trial, in which yearly intravenous zoledronic acid 5 mg was found to significantly reduce risk of various fracture types in patients with postmenopausal osteoporosis, 152 patients underwent bone biopsy. Zoledronic acid reduced bone turnover by 63% and preserved bone structure and volume, with evidence o...

Transgenic mice are an effective model to study gene function in vivo; however, position effects can complicate tissue-specific transgene analysis. To facilitate precise targeting of a transgenic construct into the mouse genome, we combined the Cre/lox and Flp/FRT recombination systems to allow for rapid transgene replacement and conditional transg...

Osteoclasts mediate bone destruction in breast cancer skeletal metastases. Cathepsin K is a proteinase that is secreted by osteoclasts and degrades bone. Here, immunohistochemistry revealed that cathepsin K was expressed not only by osteoclasts but also by breast cancer cells that metastasize to bone. Following intratibial injection with cathepsin...

Blocking TNF effectively inhibits inflammation and structural damage in human rheumatoid arthritis (RA). However, so far it is unclear whether the effect of TNF is a direct one or indirect on up-regulation of other mediators. IL-1 may be one of these candidates because it has a central role in animal models of arthritis, and inhibition of IL-1 is u...

Fat and bone metabolism are two linked processes regulated by several hormonal factors. Fetal antigen 1 (FA1) is the soluble form of dlk1 (delta-like 1), which is a member of the Notch-Delta family. We previously identified FA1 as a negative regulator of bone marrow mesenchymal stem cell differentiation. Here, we studied the effects of circulating...

Bisphosphonates exhibit direct antitumor activity in animal models, but only at high doses that are incompatible with the clinical dosing regimens approved for the treatment of cancer patients with skeletal metastases. We compared the antitumor effects of clinical dosing regimens of the bisphosphonates zoledronic acid and clodronate in a mouse mode...

Non-invasive characterization of trabecular bone structures in rodents by micro-CT is becoming increasingly popular since it is much faster than the labor-intensive histomorphometry and does not require necropsy of animals. We used vivaCT40 from Scanco Medical AG (Bassersdorf, Switzerland) to monitor changes in trabecular structure in skeletally ma...

The advent of in vivo micro-computed tomography (micro-CT) provides a novel approach to measure the temporal adaptation of bone micro-architecture within an individual. Spatial alignment in the scanner between serial scans is challenging, but three-dimensional image registration can be used to superimpose the resulting image data, thus ensuring con...

Recent evidence has demonstrated that long-term estrogen deprivation using aromatase inhibitor therapy in postmenopausal women with breast cancer results in bone loss and increased fracture risk. Bisphosphonates are potent inhibitors of bone resorption and have demonstrated efficacy in preventing bone loss in postmenopausal women with low bone mine...

The ovariectomized (OVX) rat is a well established model for osteoporosis research. The recent development of in vivo micro-computed tomography (micro-CT) provides new possibilities to monitor individual bone changes over time. The purpose of this study was to establish the normal time course of bone loss in the OVX rat model, and to determine the...

Currently available results from fracture trials provide evidence that the most potent anti-resorptive agents reduce vertebral and non-vertebral fractures maximally by 61% and 51%, respectively. Results from the Phase III trial with denosumab, the human monoclonal antibody, are eagerly awaited. Denosumab leads to sustained 80-90% reduction of bone...

Src is a nonreceptor type protein tyrosine kinase and a prototype of a family consisting of eight members in vertebrates: Src, Yes, Fyn, Fgr, Lyn, Hck, Lck, Blk. Src is an evolutionary well-conserved gene in vertebrates with homologs expressed in invertebrates. When compared with other nonreceptor type 1 tyrosine kinases in the human genome, the Sr...

Morphogenesis and remodeling of bone involve synthesis of bone matrix by osteoblasts and coordinate resorption of bone by osteoclasts. Defective bone remodeling caused by altered osteoclast activity underlies a multitude of osteopenic disorders. Receptor activator of NF-kappaB (RANK) and its ligand RANKL have been identified as essential factors in...

Characterization of trabecular bone structures requires necropsy of animals followed by a labor-intense histomorphometric or ex vivo micro-CT analysis. We tested the novel vivaCT40 from Scanco Medical AG (Bassersdorf, Switzerland), which allows monitoring such changes repeatedly in anesthetized rats and mice. Postmenopausal osteoporosis: in 8-month...

Understanding the mechanisms governing bone remodelling is essential for a clear understanding of not only pathological conditions such as osteoporosis, but also microgravity-induced bone loss. The scope of this MAP project is the further development (including technical development and biological validation) of an ex vivo culture system for trabec...

Increased osteoclast activity is a key factor in bone loss in rheumatoid arthritis (RA). This suggests that osteoclast-targeted therapies could effectively prevent skeletal damage in patients with RA. Zoledronic acid (ZA) is one of the most potent agents for blocking osteoclast function. We therefore investigated whether ZA can inhibit the bone los...

Glucocorticoids (GCs) exert potent, but poorly characterized, effects on the skeleton. The cellular activity of GCs is regulated at a prereceptor level by 11beta-hydroxysteroid dehydrogenases (11betaHSDs). The type 1 isoform, which predominates in bone, functions as a reductase in intact cells and regenerates active cortisol (corticosterone) from c...

The objective of the study was to investigate bone strength at four different skeletal sites in a chronic animal model of urinary diversion. Young male Wistar rats (120) were allocated randomly to four groups undergoing ileocystoplasty; ileocystoplasty and resection of the ileocecal segment; colocystoplasty; or sham operation (controls). After 8 mo...

Blood pH is maintained in a narrow range around pH 7.4 mainly through regulation of respiration and renal acid extrusion. The molecular mechanisms involved in pH homeostasis are not completely understood. Here we show that ovarian cancer G-protein-coupled receptor 1 (OGR1), previously described as a receptor for sphingosylphosphorylcholine, acts as...

To investigate skeletal growth and bone metabolism in a chronic animal model of urinary diversion. Young male Wistar rats (120) were allocated randomly to four groups undergoing: ileocystoplasty, ileocystoplasty and resection of the ileocaecal segment, colocystoplasty, and controls. All animals received antibiotics for 1 week after surgery; half of...

Quantitative computed tomography (QCT) is an established technique for the determination of bone mineral density (BMD) in the axial and appendicular skeleton (1). QCT is unique amongst methods of bone mineral measurement in providing separate estimates of trabecular and cortical bone mineral density as a true volumetric mineral density value (g/cm3...

The purpose of this study was to examine if substantial bone loss occurs in weaned pigs by feeding a phosphorus-deficient diet with or without fumaric acid. Eighteen weaned pigs were used. The animals were assigned to three groups: group C (control; 0.65% P on DM basis), group LP (low phosphorus; 0.37% P on DM basis) and group LPF (low phosphorus p...

Parathyroid hormone (PTH) or synthetic N-terminal PTH fragments administered intermittently have been established as anabolic agents in animal and human bones. In the present study, the influence of a low calcium diet on the anabolic effect of human PTH(1-38) [hPTH(1-38)] was investigated. Forty-eight 10-week-old female Sprague-Dawley rats were ran...

Bone marrow contains mesenchymal cells that can be isolated and grown in vitro. Using appropriate treatment protocols such cultures can be induced to differentiate to yield osteoblasts, adipocytes, and chondrocytes. However, previous experiments had not addressed the question whether single pluripotent stem cells exist and can give rise to these di...

Intermittently administered parathyroid hormone (PTH) is a potent bone anabolic agent. We aimed to determine the impact of long-term treatment with PTH on bone structure, dynamics, and mineralization. We ovariectomized (ovx) 1-year-old rats with the exception of a baseline and a sham-operated group. Twelve weeks later, a 36 week treatment with PTH...

Amylin increases bone mass when administered systemically to mice. However, because of its size, the full peptide is not an ideal candidate for the therapy of osteoporosis. The fragment, amylin-(1---8), stimulates osteoblast proliferation in vitro, although it is without effect on carbohydrate metabolism. The present study assessed the effects of d...

We report that a therapeutic dose of the antiresorptive bisphosphonate alendronate administered to skeletally mature rats for the duration of 16 weeks significantly blunted the anabolic response to a high dose SDZ PTS 893 in the tibia and femur but not in lumbar vertebra. Effects were seen at the level of bone mass (DEXA, pQCT) as well as in biomec...

The aim of the study was to assess the long-term anabolic effect of the parathyroid hormone (PTH) analog SDZ PTS 893 in a dose-response manner, and to determine the ability of the antiresorptive agents estradiol and alendronate to maintain bone mass after withdrawal of SDZ PTS 893. One hundred thirty retired breeder Wistar rats were distributed int...

Therapy for osteopenic states consists mainly of treatment with antiresorptive agents such as hormone replacement therapy, including the newly marketed selective estrogen receptor modulators, various calcitonins, and bisphosphonates. Although antiresorptive agents are powerful tools for preventing or retarding bone loss, their impact in patients wi...

(1) Could future osteoporosis research begin to account for the things described in this editorial? (2) Could agencies that give grants to support that research begin to encourage that accounting? (3) Since the FDA guidelines have great influence on what osteoporosis research is done and not done, mitht revisions of the 1994 guidelines try to ackno...

We have tested the ability of the XCT960A to detect bone loss in OVX-rats, as wel as bone gain in the proximal tibial metaphysis of healthy rats treated with hPTH(1–34). The results demonstrated that high precision can be achieved, with CV's for most measurement parameters in the range of 1.6 to 5.9% being obtained in vivo with repositioning of ani...

Lyme arthritis, one of the common features of Borrelia burgdorferi infection in the human, is associated with the production of various monocyte derived cytokines. To investigate the expression and regulation of cytokines during the acute phase of spirochete induced inflammation, a perforated Teflon chamber was implanted under the dorsal skin of se...

The aim of the study was to assess the long term effect of the antiresorptive agents estrogen and salmon calcitonin, the anabolic drug PTH, and combination therapy on vertebral bone mass and bone biomechanical competence in aged osteopenic ovariectomized (OVX) rats. Seventy-nine 1-yr-old retired breeder Wistar rats were randomized into seven groups...

Platelet-rich plasma was obtained from patients with untreated heterozygous familial hypercholesterolaemia (FH), from FH patients treated with cholestyramine and from control subjects. Responsiveness of platelets to the aggregation inhibitors adenosine, its analogue N-ethylcarboxamidoadenosine (NECA) and prostaglandin I2 was decreased in FH. Patien...