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Biomedical subjects

K Henriksen

Publications and source records attributed to K Henriksen.

At least 19 recordsLinked to original sources
PubMed2007

Osteoclasts prefer aged bone.

UNLABELLED: We investigated whether the age of the bones endogenously exerts control over the bone resorption ability of the osteoclasts, and found that osteoclasts preferentially develop and resorb bone on aged bone. These findings indicate that the bone matrix itself plays a role in targeted remodeling of aged bones. INTRODUCTION: Osteoclasts resorb aging bone in order to repair damage and maintain the quality of bone. The mechanism behind the targeting of aged bone for remodeling is not clear. We investigated whether bones endogenously possess the ability to control osteoclastic resorption. METHODS: To biochemically distinguish aged and young bones; we measured the ratio between the age-isomerized betaCTX fragment and the non-isomerized alphaCTX fragment. By measurement of TRACP activity, CTX release, number of TRACP positive cells and pit area/pit number, we evaluated osteoclastogenesis as well as osteoclast resorption on aged and young bones. RESULTS: We found that the alphaCTX/betaCTX ratio is 3:1 in young compared to aged bones, and we found that both alpha and betaCTX are released by osteoclasts during resorption. Osteoclastogenesis was augmented on aged compared to young bones, and the difference was enhanced under low serum conditions. We found that mature osteoclasts resorb more on aged than on young bone, despite unchanged adhesion and morphology. CONCLUSIONS: These data indicate that the age of the bone plays an important role in controlling osteoclast-mediated resorption, with significantly higher levels of osteoclast differentiation and resorption on aged bones when compared to young bones.

Acid Phosphatase↗
PubMed2006

Assessment of osteoclast number and function: application in the development of new and improved treatment modalities for bone diseases.

Numerous experimental and clinical observations suggest that overall changes in bone resorption during menopause or treatment with hormone replacement therapy (HRT) are combined effects of changes in osteoclast number and function. Moreover, due to a coupling between osteoclastic bone resorption and osteoblastic bone formation, pronounced alteration of osteoclast number will eventually lead to alteration of osteoblastic bone formation. Fragments of type I collagen, such as the C- and N-terminal telopeptides of collagen type I (CTX and NTX, respectively), are generated during bone resorption and hence can be used as surrogate markers of osteoclast function. Circulating levels of different enzymes in the serum, such as TRAP 5b and cathepsin K are proportional to the number of osteoclasts, and hence can be used as surrogate markers of osteoclast number. Since antiresorptive effects can be obtained in different ways, we felt it was timely to discuss the different scenarios, highlight differences specific to different pharmacological interventions with different mechanisms of action, and discuss how these bone markers can assist us in a deeper analysis of the pharmacodynamics and safety profile of existing and upcoming drug candidates.

Acid Phosphatase↗
PubMed2006

Calcitonin is involved in cartilage homeostasis: is calcitonin a treatment for OA?

OBJECTIVE: Osteoarthritis (OA) is the most common form of degenerative joint diseases and a major cause of disability and impaired quality of life in the elderly. Recent observations suggest that calcitonin may act on both osteoclasts and chondrocytes. The present review was sought to summarize emerging observations from the molecular level to the preliminary clinical findings of possible chondroprotective effects of calcitonin. METHOD: This review summarizes peer-reviewed articles found using pre-defined search criteria and published in the PubMed database before January 2006. In addition, abstracts from the OsteoArthritis Research Society International (OARSI) conferences in the time period 2000-2005 have been included in the search. RESULTS: Ample evidence for the effect of calcitonin on bone resorption was found. Support for direct effects of calcitonin on chondrocytes on matrix synthesis and inhibition of cartilage degradation have been published. In addition, clinical evidence for the effect of calcitonin on cartilage degradation is emerging. CONCLUSION: Several independent lines of evidence suggest a direct chondroprotective effect of calcitonin in addition to the well-established effect on bone resorption. Given the currently limited availability of chondroprotective agents, much expectation regards the ongoing clinical assessment of calcitonin therapy for the prevention and treatment of OA.

Animals↗
PubMed2006

Relative contribution of matrix metalloprotease and cysteine protease activities to cytokine-stimulated articular cartilage degradation.

OBJECTIVE: Both matrix metalloprotease (MMP) activity and cathepsin K (CK) activity have been implicated in cartilage turnover. We investigated the relative contribution of MMP activity and CK activity in cartilage degradation using ex vivo and in vivo models. METHODS: Bovine articular cartilage explants were stimulated with oncostatin M (OSM) 10 ng/ml and tumor necrosis factor-alpha (TNF-alpha) 20 ng/ml in the presence or absence of the broad-spectrum MMP inhibitor GM6001 and the cysteine protease inhibitor, E64. Cartilage degradation was evaluated in the conditioned medium by glycosaminoglycans (GAG), hydroxyproline, and cross-linked C-telopeptide fragments of type II collagen (CTX-II), which were compared to immunohistochemical evaluations of proteoglycans and CTX-II. We assessed MMP expression by gelatine zymography and CK expression by immunohistochemistry. In vivo, CTX-II release was measured from CK-deficient mice. RESULTS: OSM and TNF-alpha combined induced significant (P<0.01) increase in cartilage degradation products measured by hydroxyproline and CTX-II compared to vehicle control. The cytokines potently induced MMP expression, assessed by zymography, and CK expression investigated by immunohistochemistry. Inhibition of MMP activity completely abrogated hydroxyproline and CTX-II release (P<0.01) and GAG release (P<0.05). In contrast, E64 resulted in increased CTX-II release by 100% (P<0.05) and inhibited GAG release by 30%. Up-regulation of CTX-II fragments was confirmed in vivo in CK null mice. CONCLUSION: Inhibition of MMP activity reduced both proteoglycan loss and type II collagen degradation. In contrast, inhibition of cysteine proteases resulted in an increase rather than a decrease in MMP derived fragments of collagen type II degradation, CTX-II, suggesting altered collagen metabolism.

Animals↗
PubMed2006

Calcitonin directly attenuates collagen type II degradation by inhibition of matrix metalloproteinase expression and activity in articular chondrocytes.

OBJECTIVE: Calcitonin was recently reported to counter progression of cartilage degradation in an experimental model of osteoarthritis, and the effects were primarily suggested to be mediated by inhibition of subchondral bone resorption. We investigated direct effects of calcitonin on chondrocytes by assessing expression of the receptor and pharmacological effects on collagen type II degradation under ex vivo and in vivo conditions. METHODS: Localization of the calcitonin receptor on articular chondrocytes was investigated by immunohistochemistry, and the expression by reverse transcriptase polymerase chain reaction (RT-PCR). In bovine articular cartilage explants, cartilage degradation was investigated by release of C-terminal telopeptides of collagen type II (CTX-II), induced by tumor necrosis factor-alpha (TNF-alpha) [20 ng/ml] and oncostatin M (OSM) [10 ng/ml], with salmon calcitonin [0.0001-1 microM]. In vivo, cartilage degradation was investigated in ovariectomized (OVX) rats administered with oral calcitonin [2 mg/kg calcitonin] for 9 weeks. RESULTS: The calcitonin receptor was identified in articular chondrocytes by immunohistochemistry and RT-PCR. Calcitonin concentration-dependently increased cAMP levels in isolated chondrocytes. Explants cultured with TNF-alpha and OSM showed a 100-fold increase in CTX-II release compared to vehicle-treated controls (P<0.001). The degradation of type II collagen in these explants was concentration-dependently inhibited by calcitonin, 65% protection at 10 nM calcitonin (P<0.01). TNF-alpha and OSM induced a pronounced increase in matrix metalloproteinase (MMP) activity, which was strongly inhibited by calcitonin. In vivo, administration of salmon calcitonin to OVX rats resulted in significant (P<0.001) decrease in CTX-II levels. CONCLUSION: These results are the first evidence of calcitonin receptor expression on articular chondrocytes and that the chondroprotective effects of calcitonin might involve the inhibition of MMP expression.

Animals↗
PubMed2006

Estrogen directly attenuates human osteoclastogenesis, but has no effect on resorption by mature osteoclasts.

Estrogen deficiency arising with the menopause promotes marked acceleration of bone resorption, which can be restored by hormone replacement therapy. The inhibitory effects of estrogen seem to involve indirect cytokine- mediated effects via supporting bone marrow cells, but direct estrogen-receptor mediated effects on the bone-resorbing osteoclasts have also been proposed. Little information is available on whether estrogens modulate human osteoclastogenesis or merely inhibit the functional activity of osteoclasts. To clarify whether estrogens directly modulate osteoclastic activities human CD14+ monocytes were cultured in the presence of M-CSF and RANKL to induce osteoclast differentiation. Addition of 0.1-10 nM 17beta-estradiol to differentiating osteoclasts resulted in a dose-dependent reduction in tartrate resistant acid phosphatase (TRACP) activity reaching 60% at 0.1 nM. In addition, 17beta-estradiol inhibited bone resorption, as measured by the release of the C-terminal crosslinked telopeptide (CTX), by 60% at 0.1 nM, but had no effect on the overall cell viability. In contrast to the results obtained with differentiating osteoclasts, addition of 17beta-estradiol (0.001-10 nM) to mature osteoclasts did not affect bone resorption or TRACP activity. We investigated expression of the estrogen receptors, using immunocytochemistry and Western blotting. We found that ER-alpha is expressed in osteoclast precursors, whereas ER- beta is expressed at all stages, indicating that the inhibitory effect of estrogen on osteoclastogenesis is mediated by ER-alpha for the major part. In conclusion, these results suggest that the in vivo effects of estrogen are mediated by reduction of osteoclastogenesis rather than direct inhibition of the resorptive activity of mature osteoclasts.

Blotting, Western↗
PubMed2006

Issues in the design of training for quality and safety.

The US healthcare delivery system is in a state of change. Medical science and technology are advancing at an unprecedented rate, while cost containment and productivity pressures on clinicians make the clinical environment less than ideal for training. Training is one of the vehicles for addressing new knowledge requirements and for enhancing human and system based performance. Yet the theoretical underpinnings and design aspects of training have been largely unrecognized and unexamined in health care. This paper first explores changes in the practice of medicine and the healthcare delivery environment. It then describes how healthcare training and education can benefit from findings in the behavioral and cognitive sciences. It describes the systems approach to training and explores the extent to which a systems approach can be applied to the clinical environment. Finally, the paper examines innovative training and education techniques that are already gaining acceptance in health care.

Curriculum↗
PubMed2005

In vitro, ex vivo, and in vivo methodological approaches for studying therapeutic targets of osteoporosis and degenerative joint diseases: how biomarkers can assist?

Although our approach to the clinical management of osteoporosis (OP) and degenerative joint diseases (DJD)-major causes of disability and morbidity in the elderly-has greatly advanced in the past decades, curative treatments that could bring ultimate solutions have yet to be found or developed. Effective and timely development of candidate drugs is a critical function of the availability of sensitive and accurate methodological arsenal enabling the recognition and quantification of pharmacodynamic effects. The established concept that both OP and DJD arise from an imbalance in processes of tissue formation and degradation draws attention to need of establishing in vitro, ex vivo, and in vivo experimental settings, which allow obtaining insights into the mechanisms driving increased bone and cartilage degradation at cellular, organ, and organism levels. When addressing changes in bone or cartilage turnover at the organ or organism level, monitoring tools adequately reflecting the outcome of tissue homeostasis become particularly critical. In this context, bioassays targeting the quantification of various degradation and formation products of bone and cartilage matrix elements represent a useful approach. In this review, a comprehensive overview of widely used and recently established in vitro, ex vivo, and in vivo set-ups is provided, which in many cases effectively take advantage of the potentials of biomarkers. In addition to describing and discussing the advantages and limitations of each assay and their methods of evaluation, we added experimental and clinical data illustrating the utility of biomarkers for these methodological approaches.

Animals↗
PubMed2005

The role of chloride channels in osteoclasts: ClC-7 as a target for osteoporosis treatment.

Chloride ions play a major role in osteoclast biology and bone homeostasis. In addition to its general cellular roles, chloride is involved in the specific bone resorption activity of osteoclasts. The chloride channel ClC-7 has been shown to be mandatory for bone resorption. It is necessary for the acidification of the resorption lacunae. In addition to ClC-7, other chloride channels and exchangers have been identified in osteoclasts. The bicarbonate-chloride exchanger at the plasma membrane of osteoclasts is important for regulating the cytoplasmic pH during bone resorption. The role of the additional chloride channels or putative chloride channels identified in osteoclasts, volume-regulated anion channel, Chlor.62 and CLIC1 has not been established. To date, ClC-7 is the only known chloride channel whose disruption or mutation leads to a bone disease: osteopetrosis, which is characterized by an increased bone mass. Inhibition of ClC-7 constitutes a new potential way to treat osteoporosis. The expression of ClC-7 is restricted to few tissues with very high expression in the osteoclasts in bone. Pharmacologically, inhibitors of acidification of the resorption lacunae have proved to be unique, as inhibition leads to a decrease in bone resorption without affecting bone formation, suggesting that the coupling principle has been challenged. Thus, ClC-7 inhibitors may prove to be potent for prevention and treatment of osteoporosis.

Animals↗
PubMed2003

Hindsight bias, outcome knowledge and adaptive learning.

The ubiquitous nature of hindsight bias is a cause for concern for those engaged in investigations and retrospective analysis of medical error. Hindsight does not equal foresight. Investigations that are anchored to outcome knowledge run the risk of not capturing the complexities and uncertainties facing sharp end personnel and why their actions made sense at the time. Important lessons go unlearned if the exercise is simply to back track someone else's decision landmarks. Outcome knowledge can also bias our thinking on the quality of the processes that led to the outcome. This paper examines the influence of outcome knowledge in relation to reconstructive memory and legal testimony, ways for reducing the impact of outcome knowledge, and an adaptive learning framework that places hindsight bias in a broader context of rapid updating of knowledge.

Adaptation, Psychological↗
PubMed2001

Degradation of 4-nonylphenol in homogeneous and nonhomogeneous mixtures of soil and sewage sludge.

Sewage sludge is frequently applied as fertilizers to cultivated land. However, municipal sewage sludge often contains organic contaminants including nonylphenol (NP), an intermediate from nonionic surfactant degradation. Knowledge about NP degradation in sludge-amended soil is an important prerequisite for adequate risk assessments. In this study, mineralization of 14C-labeled NP in homogenized and nonhomogenized sludge-soil mixtures was investigated. NP was degraded within 38 days in aerobic homogenized mixtures. In nonhomogeneous mixtures containing sludge aggregates, the degradation of NP was retarded and was generally not completed within 3 months (119-126 days). No detectable amounts of NP were transported from the sludge aggregates to the surrounding soil (detection limit: <0.04 mg of NP/kg dw of soil). Oxygen penetration into sludge aggregates was monitored for 50 days with an oxygen microelectrode. An extrapolation of the oxygen data suggested that more than 1 year was required to obtain fully aerobic conditions in a 2-cm sludge aggregate. Since NP is considered persistent in the absence of oxygen, residual amounts of NP may be present in the anaerobic center of aggregates for prolonged periods. The results demonstrate that sludge aggregate size and thus oxygen availability will be a major controlling factor for NP degradation in soil amended with sewage sludge and that the mobility of NP from sludge aggregates to the surrounding soil is negligible.

Agriculture↗
PubMed2001

Toxic effects of linear alkylbenzene sulfonate on metabolic activity, growth rate, and microcolony formation of Nitrosomonas and Nitrosospira strains.

Strong inhibitory effects of the anionic surfactant linear alkylbenzene sulfonate (LAS) on four strains of autotrophic ammonia-oxidizing bacteria (AOB) are reported. Two Nitrosospira strains were considerably more sensitive to LAS than two Nitrosomonas strains were. Interestingly, the two Nitrosospira strains showed a weak capacity to remove LAS from the medium. This could not be attributed to adsorption or any other known physical or chemical process, suggesting that biodegradation of LAS took place. In each strain, the metabolic activity (50% effective concentration [EC(50)], 6 to 38 mg liter(-1)) was affected much less by LAS than the growth rate and viability (EC(50), 3 to 14 mg liter(-1)) were. However, at LAS levels that inhibited growth, metabolic activity took place only for 1 to 5 days, after which metabolic activity also ceased. The potential for adaptation to LAS exposure was investigated with Nitrosomonas europaea grown at a sublethal LAS level (10 mg liter(-1)); compared to control cells, preexposed cells showed severely affected cell functions (cessation of growth, loss of viability, and reduced NH(4)(+) oxidation activity), demonstrating that long-term incubation at sublethal LAS levels was also detrimental. Our data strongly suggest that AOB are more sensitive to LAS than most heterotrophic bacteria are, and we hypothesize that thermodynamic constraints make AOB more susceptible to surfactant-induced stress than heterotrophic bacteria are. We further suggest that AOB may comprise a sensitive indicator group which can be used to determine the impact of LAS on microbial communities.

Alkanesulfonic Acids↗
PubMed2000

Matrix metalloproteinase 9 and vascular endothelial growth factor are essential for osteoclast recruitment into developing long bones.

Bone development requires the recruitment of osteoclast precursors from surrounding mesenchyme, thereby allowing the key events of bone growth such as marrow cavity formation, capillary invasion, and matrix remodeling. We demonstrate that mice deficient in gelatinase B/matrix metalloproteinase (MMP)-9 exhibit a delay in osteoclast recruitment. Histological analysis and specialized invasion and bone resorption models show that MMP-9 is specifically required for the invasion of osteoclasts and endothelial cells into the discontinuously mineralized hypertrophic cartilage that fills the core of the diaphysis. However, MMPs other than MMP-9 are required for the passage of the cells through unmineralized type I collagen of the nascent bone collar, and play a role in resorption of mineralized matrix. MMP-9 stimulates the solubilization of unmineralized cartilage by MMP-13, a collagenase highly expressed in hypertrophic cartilage before osteoclast invasion. Hypertrophic cartilage also expresses vascular endothelial growth factor (VEGF), which binds to extracellular matrix and is made bioavailable by MMP-9 (Bergers, G., R. Brekken, G. McMahon, T.H. Vu, T. Itoh, K. Tamaki, K. Tanzawa, P. Thorpe, S. Itohara, Z. Werb, and D. Hanahan. 2000. Nat. Cell Biol. 2:737-744). We show that VEGF is a chemoattractant for osteoclasts. Moreover, invasion of osteoclasts into the hypertrophic cartilage requires VEGF because it is inhibited by blocking VEGF function. These observations identify specific actions of MMP-9 and VEGF that are critical for early bone development.

Animals↗
PubMed1999

Characterization of methanotrophic bacterial populations in soils showing atmospheric methane uptake.

The global methane cycle includes both terrestrial and atmospheric processes and may contribute to feedback regulation of the climate. Most oxic soils are a net sink for methane, and these soils consume approximately 20 to 60 Tg of methane per year. The soil sink for atmospheric methane is microbially mediated and sensitive to disturbance. A decrease in the capacity of this sink may have contributed to the approximately 1%. year(-1) increase in the atmospheric methane level in this century. The organisms responsible for methane uptake by soils (the atmospheric methane sink) are not known, and factors that influence the activity of these organisms are poorly understood. In this study the soil methane-oxidizing population was characterized by both labelling soil microbiota with (14)CH(4) and analyzing a total soil monooxygenase gene library. Comparative analyses of [(14)C]phospholipid ester-linked fatty acid profiles performed with representative methane-oxidizing bacteria revealed that the soil sink for atmospheric methane consists of an unknown group of methanotrophic bacteria that exhibit some similarity to type II methanotrophs. An analysis of monooxygenase gene libraries from the same soil samples indicated that an unknown group of bacteria belonging to the alpha subclass of the class Proteobacteria was present; these organisms were only distantly related to extant methane-oxidizing strains. Studies on factors that affect the activity, population dynamics, and contribution to global methane flux of "atmospheric methane oxidizers" should be greatly facilitated by use of biomarkers identified in this study.

Amino Acid Sequence↗
PubMed1998

Degradation of phthalate and Di-(2-Ethylhexyl)phthalate by indigenous and inoculated microorganisms in sludge-amended soil

The metabolism of phthalic acid (PA) and di-(2-ethylhexyl)phthalate (DEHP) in sludge-amended agricultural soil was studied with radiotracer techniques. The initial rates of metabolism of PA and DEHP (4.1 nmol/g [dry weight]) were estimated to be 731.8 and 25.6 pmol/g (dry weight) per day, respectively. Indigenous microorganisms assimilated 28 and 17% of the carbon in [14C]PA and [14C]DEHP, respectively, into microbial biomass. The rates of DEHP metabolism were much greater in sludge assays without soil than in assays with sludge-amended soil. Mineralization of [14C]DEHP to 14CO2 increased fourfold after inoculation of sludge and soil samples with DEHP-degrading strain SDE 2. The elevated mineralization potential was maintained for more than 27 days. Experiments performed with strain SDE 2 suggested that the bioavailability and mineralization of DEHP decreased substantially in the presence of soil and sludge components. The microorganisms metabolizing PA and DEHP in sludge and sludge-amended soil were characterized by substrate-specific radiolabelling, followed by analysis of 14C-labelled phospholipid ester-linked fatty acids (14C-PLFAs). This assay provided a radioactive fingerprint of the organisms actively metabolizing [14C]PA and [14C]DEHP. The 14C-PLFA fingerprints showed that organisms with different PLFA compositions metabolized PA and DEHP in sludge-amended soil. In contrast, microorganisms with comparable 14C-PLFA fingerprints were found to dominate DEHP metabolism in sludge and sludge-amended soil. Our results suggested that indigenous sludge microorganisms dominated DEHP degradation in sludge-amended soil. Mineralization of DEHP and PA followed complex kinetics that could not be described by simple first-order equations. The initial mineralization activity was described by an exponential function; this was followed by a second phase that was described best by a fractional power function. In the initial phase, the half times for PA and DEHP in sludge-amended soil were 2 and 58 days, respectively. In the late phase of incubation, the apparent half times for PA and DEHP increased to 15 and 147 days, respectively. In the second phase (after more than 28 days), the half time for DEHP was 2.9 times longer in sludge-amended soil assays than in sludge assays without soil. Experiments with radiolabelled DEHP degraders suggested that a significant fraction of the 14CO2 produced in long-term degradation assays may have originated from turnover of labelled microbial biomass rather than mineralization of [14C]PA or [14C]DEHP. It was estimated that a significant amount of DEHP with poor biodegradability and extractability remains in sludge-amended soil for extended periods of time despite the presence of microorganisms capable of degrading the compound (e.g., more than 40% of the DEHP added is not mineralized after 1 year).

Journal Article↗
PubMed1997

Apoptosis in human acute myocardial infarction.

BACKGROUND: After reopening of the infarct-related coronary artery, cardiomyocytes continue to die during reperfusion. The mechanisms of cell death have been subject to debate. We studied whether an apoptotic type of cell death occurs in human acute myocardial infarction (AMI). METHODS AND RESULTS: We studied myocardial samples of eight patients who died of AMI and had patent infarct-related arteries at autopsy. Six of the patients had received initially successful thrombolysis. Extensive formation of DNA strand breaks, the typical biochemical feature of apoptosis, was detected with the use of the in situ DNA end-labeling method. Apoptotic cardiomyocytes were observed particularly in the border zones of histologically infarcted myocardium, whereas very few apoptotic cells were present in the remote noninfarcted myocardium. Internucleosomal fragmentation was confirmed by agarose gel electrophoresis of DNA isolated from the representative myocardial areas. CONCLUSIONS: This study provides evidence that in addition to overt necrosis, a subset of myocytes undergo apoptosis during ischemia-reperfusion injury. Apoptosis may provide a new target for cardioprotection during evolving AMI in humans.

Adult↗