Molecular mechanisms of bone resorption. An update.
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Actins↗
Biomedical subjects
R Baron
Publications and source records attributed to R Baron.
Normative data for muscle strength in relation to age, knee angle and velocity.
Standardized normal values are necessary to assess the performance with respect to the momentary functional state as well as a documentation of a training or rehabilitation program. The isokinetic extension strength of the right and left knee was investigated in 147 healthy male subjects between 17 and 70 years who were divided into 6 age groups. Normative data are given in dependence on age, knee angle and various velocities and regression equation in relation to the knee angle and for the peak torque in relation to the angular velocity. We found a significant decrease in maximum torque with increasing angle acceleration (p < 0.001) and a correlation between strength and body mass (p < 0.05). The highest values were found in the group of 20- to 29-year olds, while the strength was lower up to age 20. The decrease in force between 25 to 70 years ranges up to 37% at a velocity of 10 degrees/s, up to 41% at a velocity of 60 degrees/s and up to 50% at a velocity of 180 degrees/s.
Adolescent↗
Metabolic and cardiorespiratory reactions in tennis-players in laboratory testing and under sport-specific conditions.
Metabolic and cardiorespiratory reactions were investigated during a sport-specific incremental field test (FT) for tennis and compared with a treadmill step test (TT) in a group of 13 trained male tennis players. In both the FT and the TT lactate acid (La), heart rate and oxygen uptake (VO2) were measured. VO2 was determined using a portable telemetric system (K2, Cosmed, Italy). Aerobic- (AT) and anaerobic threshold (ANT) at a blood lactate concentration of 2 mmol/l and at 4 mmol/l respectively was indicated to characterize the endurance capacity of the athletes. In both FT and TT, minimum value of lactate equivalent (LE(min)), measured in every exercise test, was also registered. At AT and ANT values for HR (AT: p < 0.001; ANT: p < 0.001) and VO2 (AT: p < 0.001; ANT: p < 0.001) were significantly higher in FT than in TT at submaximal loads. At LE(min) only higher values for HR (p < 0.05) were registered in FT. In contrast to maximum range significantly higher values for VO2 (p < 0.001) could be seen in TT (there were no significant differences for HR). Comparing maximum lactate (La(max)) subjects reached a higher lactate (p < 0.05) in TT. A particular aim of our investigation was to characterize the individual cardiopulmonal and metabolic adaptation of tennis players, considering sport-specific criteria. As a result, differences in cardiorespiratory and metabolic adaptations could be determined between laboratory TT and FT. This finding seems to point to the fact that, using field testing in addition to laboratory exercise testing, makes a better judgement of aerobic and anaerobic endurance under sport-specific conditions possible. Furthermore, it was important for us to put data, determined in the field test into practice, using the given pattern of the field test as an element of training. This kind of training has the advantage of combining an individually intensity-controlled specific endurance training for tennis with a training of technical skills.
Adult↗
The catalytic cycle of the vacuolar H(+)-ATPase. Comparison of proton transport in kidney- and osteoclast-derived vesicles.
To characterize the catalytic cycle involved in the initial rate of proton transport by the vacuolar ATPases (V-ATPase), we have analyzed and compared the catalytic parameters of V-ATPase-dependent proton transport in vesicles from chicken kidney or purified osteoclasts. The relationship of acidification to ATP obeyed simple Michaelis-Menten kinetics with a single Km for ATP of 62 microM in the kidney and 191 microM in the osteoclast. The activity was dependent on the presence of Mg2+, with a single Km of 258 microM MgCl2 in the kidney and 504 microM MgCl2 in the osteoclast. In both preparations, ADP competed with ATP and inhibited the proton transport (Ki = 37 microM in kidney and 17 microM in osteoclast). Phosphate was found to be a noncompetitive inhibitor of ATP, with a calculated Ki of about 10.5 and 5.5 mM, respectively. In both preparations, the catalytic mechanism determining the V-ATPase-mediated proton transport, fits the model of a "uni-bi-ordered release" mechanism. According to this model, ATP is the single substrate, and P(i) and ADP are the two products where phosphate, being noncompetitive, is released first and ADP, being competitive, second. The findings of an elevated Km for ATP and Mg2+ and a decrease in the Ki of ADP and phosphate in the osteoclast relative to the kidney preparation suggests that the V-ATPases present in these two tissues may differ.
Adenosine Diphosphate↗
[Endoscopic transthoracic sympathectomy in a paraneoplastic Raynaud's syndrome].
Six months after nephrectomy for renal-cell carcinoma and during treatment with interferon-alpha and vinblastin, a 70-year-old patient developed necrotizing Raynaud's phenomenon in both hands (at first: pain, livid skin and hyperhidrosis; later: painful acral ulcers; finally: trophic changes plus almost complete impairment of mobility and fine movements in both hands). These changes persisted even after the end of chemotherapy and despite several months on aspirin, naftidrofuryl, nitrates and glucocorticoids, so that the patient's general health was seriously affected. Because repeated sympathetic blocks were efficacious for brief periods, bilateral transthoracic endoscopic sympathectomy (TES) was performed. The patient became free of pain at once, the acral ulcers healed within a few weeks and he could again use his hands. Until his death from advanced metastases 10 months later the Raynaud's phenomenon did not recur. This case suggests that sympathetic vasoconstriction is apparently involved in the maintenance and progression of malignant neoplasm-associated Raynaud's phenomenon. TES is recommended as a reasonable palliative measure in patients with limited life expectancy, as long as preceding sympathetic blockage has indicated likely success and the procedure is performed under intraoperative monitoring of acral and facial skin temperature.
Aged↗
Cell cycle-dependent and kinase-specific regulation of the apical Na/H exchanger and the Na,K-ATPase in the kidney cell line LLC-PK1 by calcitonin.
Calcitonin (CT), which regulates serum calcium through its actions in bone and the kidney tubule, also has a potent natriuretic effect in vivo. Na reabsorption in the proximal kidney tubule is mostly dependent on the activity of the Na,K-ATPase and the apical Na/H exchanger. We have previously shown that CT regulates the activity of the Na,K-ATPase in the proximal kidney tubule cell line LLC-PK1 in a cell cycle-dependent manner. We report here that, in the same cells, CT also regulates the Na/H exchanger through a cell cycle-specific activation of the Ca/calmodulin-dependent protein kinase II. In G2 phase, no changes in ethylisopropyl amiloride-sensitive 22Na uptake is observed, despite an increase in cAMP. In contrast, the hormone inhibits the apical exchanger when the cells are in S phase, resulting in an 80% inhibition of 22Na uptake. These results demonstrate that CT affects the activity of the two major proximal tubule Na transport systems and may help clarify the mechanisms by which CT regulates Na+ reabsorption.
Animals↗
Axon-reflex reactions in affected and homologous contralateral skin after unilateral peripheral injury of thoracic segmental nerves in humans.
Transection and regeneration of a rat peripheral nerve on one side reduces the ability of the contralateral nerve to evoke plasma extravasation after antidromic excitation of afferent C-fibers induced by electrical nerve stimulation (afferent axon reflex). An unknown transneuronal signalling substance was postulated. In humans, axon-reflex vasodilatation was studied using cutaneous iontophoresis of histamine for C-fiber stimulation and laser Doppler flowmetry for measuring vasodilatation. As a model of peripheral nerve lesion with regeneration, patients with severe unilateral zoster neuropathy of thoracic segmental nerves were examined. Axon-reflex reactions were considerably impaired within the affected dermatome compared with the unaffected side and compared with controls. In contrast, no significant differences could be found between the unaffected corresponding sites of patients and similar dermatomes of healthy controls, indicating that this type of nerve injury does not influence the ability of the contralateral nerve to evoke axon-reflex vasodilatation.
Aged↗
The constant velocity translatoric dynamo ergometer. A new approach to investigate neuromuscular, metabolic, and cardiovascular parameters.
The goal of this study was to investigate with the new dynamo ergometer the forces produced within a defined range of motion at a constant velocity during concentric translatoric work as well as to investigate fatigue based on neuromuscular and metabolic parameters. We examined 11 male sports students with the "Motomir" device with the subjects in a sitting position. The test consisted of four times 1 min of concentric leg work with 1-min rest phases in between. The subjects were asked to do maximum effort push movements with one leg and maximum effort pull movements with the other leg. The translatoric form of movement did not reveal any significant differences in strength between the left and right legs. The strength of the extensors was significantly higher than that of the flexors during all exercise stages (p < 0.001). A significant decrease in strength was established for extensor muscles and no significant decrease for the flexor muscles. The quotient of flexor/extensor was 0.43 +/- 0.07 in the first exercise stage and increased in every stage till the fourth. There was a correlation (p < 0.001) between the difference in lactate of the first and fourth exercise stages and the percentage of force decrease from the 1st to the 4th min. The electric activity of the vastus medialis, vastus lateralis, and gastrocnemius muscles decreased from the first to the fourth exercise stage. This decrease was however not significant. The translatoric constant velocity dynamo ergometer allows both diagnosis and training at varying angles and varying speeds while avoiding unphysiological maximum loads.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
[Comments on the paper by P. Hügler et al. The therapy of postherpetic zoster neuralgia].
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Aged↗
Sensitivity to nitrate and other oxyanions further distinguishes the vanadate-sensitive osteoclast proton pump from other vacuolar H(+)-ATPases.
The osteoclast proton pump (OC H(+)-ATPase) differs from other vacuolar H(+)-ATPases (V-ATPases) in its sensitivity to vanadate and in the subunit composition of its catalytic domain, where isoforms of subunits A and B are expressed [Chatterjee et al. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 6257-6261]. In the present study, the sensitivity of the osteoclast H(+)-ATPase to various oxyanions was tested. The results indicate that H+ transport by microsomal preparations isolated from chicken osteoclasts is 20-100-fold more sensitive to nitrate that any other animal and fungal V-ATPases and 10-20-fold more sensitive than plant V-ATPases, as is the ATPase activity of the affinity-purified enzyme. This inhibition by nitrate is not due to a chaotropic effect of the oxyanion and is complete at 1 mM concentrations with an IC50 of 100 microM. In contrast, proton transport by the OC H(+)-ATPase was insensitive to other oxyanions (phosphate, sulfate, and acetate) which inhibit other V-ATPases. These results further demonstrate that the proton pump present in osteoclast membranes differs from other vacuolar ATPases. It is speculated that, since cells of the macrophage lineage can generate high intracellular concentrations of nitrate, it may be possible to physiologically or therapeutically regulate the activity of the OC H(+)-ATPase in the osteoclast without affecting the other V-ATPases in the same or in other cells.
Animals↗
Macrophage colony-stimulating factor release and receptor expression in bone cells.
Colony-stimulating factors (CSF) may play a role in bone resorption. To examine whether osteoblasts secrete colony-stimulating activity (CSA) in response to parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP), conditioned medium (CM) from ROS 17/2.8 cells and primary rat osteoblasts were examined for induction of clonal growth of cultured rat bone marrow cells. Untreated cells constitutively secreted CSA, which increased with PTH and PTHrP treatment. The colonies formed were principally comprised of macrophages, and preincubation of CM with antiserum to murine macrophage colony-stimulating factor (M-CSF) neutralized most of the CSA, suggesting that the osteoblast-derived CSA was predominantly due to M-CSF. PTHrP treatment upregulated steady-state M-CSF mRNA levels. To investigate a paracrine role for M-CSF in bone we examined bone tissue and cells for the M-CSF receptor c-fms using immunohistochemical techniques and demonstrated staining of mature osteoclasts both in situ and after isolation. We conclude that M-CSF is responsible for the majority of the CSA released by PTH- and PTHrP-treated rat osteoblasts. In addition we identified CSF-1 receptor expression in mature osteoclasts. These data suggest that M-CSF is a mediator of osteoblast-osteoclast interaction in PTH- and PTHrP-induced bone resorption.
Animals↗
Mice transgenic for HTLV-I LTR-tax exhibit tax expression in bone, skeletal alterations, and high bone turnover.
HTLV-I infection can result in adult T cell leukemia with accompanying hypercalcemia and increased bone resorption. A viral etiology has also been invoked for Paget's disease, a disease of high bone turnover. Delineation of pathogenetic mechanisms of viral-associated bone diseases has been impeded by the complexity of viral and host factors. In order to consider the relationship of HTLV-I infection to skeletal changes we have evaluated the role of a single viral gene in mice transgenic for HTLV-I tax under the control of the viral promoter. Tax mice exhibited severe skeletal abnormalities characterized by high bone turnover, increases in osteoblast and osteoclast numbers and activity, and myelofibrosis. These changes were apparent as early as two months of age. Tax mRNA and protein were highly expressed in bone but not in bone marrow nor in any other tissues except, as previously reported, salivary gland and neurofibromas when they did develop. Within bone, tax protein was detected in only two cell types, mature osteoclasts and spindle-shaped cells within the endosteal myelofibrosis. These observations suggest that local expression of the tax gene, which encodes a viral regulatory protein known to influence host gene expression, can induce within the bone environment marked changes in bone cell activity, resulting in profound skeletal alterations.
Animals↗
Small fibre function in primary autonomic failure.
A case of primary autonomic failure (AF) with uncomplicated Parkinson's disease is presented with clinical and neurophysiological data. Special emphasis is placed on new methods of examining impairment of unmyelinated sympathetic and afferent C-fibres. Sympathetic vasoconstrictor responses in the skin induced by deep inspiration were examined quantitatively with laser Doppler flowmetry. The vasoconstriction was markedly depressed in primary AF compared with healthy controls and similar to secondary forms of AF. Peripheral nociceptive C-fibre function was quantitatively assessed by measurement of axon reflex vasodilatation induced by histamine iontophoresis. The axon reflex vasodilatation was completely intact in primary AF in contrast to patients with secondary peripheral small fibre neuropathy. The results indicate that sympathetic C-fibres are considerably affected by the degenerative disease, whereas the afferent C-fibres seem to be totally preserved. Modern neurophysiological methods of testing sympathetic and afferent small fibre function in combination with other neurophysiological tests, e.g. brain-stem auditory evoked potentials, might help to diagnose and differentiate primary AF in early stages and make it easier to distinguish between secondary autonomic neuropathies of unknown origin that often also involve unmyelinated afferent fibres.
Afferent Pathways↗
Postherpetic neuralgia. Are C-nociceptors involved in signalling and maintenance of tactile allodynia?
Under normal conditions acute stimulation and sensitization of polymodal nociceptive C-fibres cause pain and, due to afferent axon reflex activation, a local skin vasodilatation, flare reaction and skin temperature increase. Two questions arise: (i) Do sensitized C-nociceptors signal allodynia in chronic postherpetic neuralgia? (ii) If not, does ongoing peripheral nociceptive C-fibre input maintain a central process that accounts for allodynia? Ten patients with postherpetic neuralgia and tactile allodynia and 10 control subjects were studied using a laser Doppler perfusion monitor. Peripheral nociceptive C-fibre function was assessed by quantitative measurement of the axon reflex vasodilatation and flare reaction induced by histamine iontophoresis and compared with non-neural vasodilatation induced by local skin heating. Resting skin temperature, skin resistance and resting skin blood flow were the same in the allodynic area and the contralateral homologous skin area. The histamine responses (vasodilatation and flare) were significantly reduced or nearly abolished in the allodynic area compared with the contralateral side, whereas the temperature-dependent vasodilatation in patients and the histamine responses in healthy controls showed no side differences. C-fibre mediated pain and itch sensations were also decreased in the allodynic area. These findings indicate a considerable impairment of cutaneous nociceptive C-fibre function in the allodynic area. Allodynic stimuli of 20 s did not cause any local blood flow change. Impairment of C-fibre function was positively correlated with intensity of neuropathic pain. We conclude that sensitized nociceptive C-fibres are not involved in signalling allodynia. Changes in CNS processing may occur after zoster infection that strengthen the synaptic ties between central pain signalling pathways and low-threshold mechanoreceptors with A beta-fibres. This altered central processing is not maintained by ongoing cutaneous nociceptive C-fibre input, at least in some patients with postherpetic neuralgia. On the contrary, an anatomical synaptic reorganization depending on afferent C-fibre degeneration seems to be more likely, particularly in advanced stages of postherpetic neuralgia.
Aged↗
(Pro)collagenase (matrix metalloproteinase-1) is present in rodent osteoclasts and in the underlying bone-resorbing compartment.
Osteoclasts resorb the extracellular matrix of bone by secreting enzymes and acid into a sealed-off compartment that they form upon attachment to the bone surface. Although the lysosomal cysteine proteinases can degrade collagen after the demineralization of bone at low pH, several lines of evidence suggest that collagenase (matrix metalloproteinase-1, EC 3.4.24.7) may also be involved in this process. The question of whether collagenase is present in the osteoclast and/or in the bone-resorbing compartment has however not been resolved. We have prepared an anti-mouse collagenase antiserum and affinity-purified an IgG fraction that specifically immunoblots and immunoprecipitates (pro)collagenase. Using these antibodies, we demonstrate by immunolocalization the presence of (pro)collagenase both in the osteoclasts and in the extracellular subosteoclastic bone-resorbing compartment. These specific localizations were observed not only in mice but also in rat and rabbit osteoclasts and using not only the antibody we have prepared but also antibodies raised in other laboratories against rat (Jeffrey et al., J. Cell. Physiol. 143, 396-403, 1990) and rabbit (Brinckerhoff et al., J. Biol. Chem. 265, 22262-22269, 1990) collagenase. Intracellular collagenase was observed in the osteoclasts whether the cells were plated on bone or cultured on glass coverslips. It is proposed that osteoclastic collagenase is secreted in the resorbing compartment where it may cooperate with the lysosomal cysteine proteinases in the degradation of the collagen component of the matrix during the resorption of bone.
Animals↗
[Principles of muscle efficiency in weightlessness].
Depending on the time spent in a space station, weightlessness causes varying changes to various organs and regulatory mechanisms of the human organism, among them the structures of the active and passive locomotor system. Experience has shown that regular physical activity using varying forms of training is necessary to keep astronauts and cosmonauts healthy, efficient and fit for work and to prepare them for a safe return to terrestrial conditions. One of the main tasks of physical activity is therefore to counteract the changes in the neuromuscular function, muscle strength, endurance and fatigability under conditions of weightlessness. So far, the diagnostics of these changes was limited to dynamometric measurements before and after space flights as no dynamometric method had been devised which was precise enough under conditions of weightlessness. The development and the introduction of the dynamoergometer Motomir is described against the background of previous results obtained by dynamometric, ergometric, morphometric, biochemical, histochemical and neuromuscular examinations before and after missions of varying duration under conditions of weightlessness. This device was used for the first valid and reproducible examinations of muscle strength and endurance aboard the space station Mir during the Austro-Russian space mission Austromir. The results of the examinations with this speed-controlled dynamometer and training device obtained during a short-term flight of 10 days and a long-term flight of 6 months are described and compared to previous results in the literature. Based on the existing training devices, training methods and training plans and the results of the Motomir Study, plans for devices and methodologies for future long-term space flights of up to 3 years' duration will be discussed. Finally, the possible use of a speed-controlled dynamometer and training device for rehabilitation on earth after injuries, surgery and immobilization of the active and passive locomotor system as well as in the bed-rest syndrome is being presented.
Animals↗
[Germs responsible for nosocomial infections].
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Cross Infection↗
Sensitivity to vanadate and isoforms of subunits A and B distinguish the osteoclast proton pump from other vacuolar H+ ATPases.
Analysis of proton (H+) transport by inside-out vesicles derived from highly purified chicken osteoclast (OC) membranes has revealed the presence of a newly discovered type of vacuolar H+ ATPase (V-ATPase). Unlike vesicles derived from any other cell type or organelle, H+ transport in OC-derived vesicles is sensitive to V-ATPase inhibitors (N-ethylmaleimide and Bafilomycin A1) and vanadate (IC50, 100 microM), an inhibitor previously found to affect only P-type ATPases. The OC H+ ATPase contains several V-like subunits (115, 39, and 16 kDa) but subunits A and B of the catalytic domain of the enzyme differ from that of other V-ATPases. In OCs, subunit A has a mass of 63 kDa instead of the 67-70 kDa expressed in monocytes, macrophages, and kidney microsomes, which contain a vanadate-insensitive H+ ATPase. Moreover, two types of 57- to 60-kDa B subunits are also found: one is expressed predominantly in OCs and the other is expressed in kidney microsomes. The OC H+ pump may therefore constitute a class of H+ ATPase with a unique pharmacology and specific isoforms of two subunits in the catalytic portion of the enzyme. This H+ ATPase is involved in resorption of bone and may be expressed in a cell-specific manner, thereby opening possibilities for therapeutic intervention.
Animals↗