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Dive into the research topics where Kalervo Väänänen is active.

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Featured researches published by Kalervo Väänänen.


Biochemical and Biophysical Research Communications | 1990

Inhibition of osteoclast proton transport by bafilomycin A1 abolishes bone resorption

Kai T. Sundquist; Päivi T. Lakkakorpi; Björn Wallmark; Kalervo Väänänen

Osteoclasts are the main bone resorbing cells with capacity to acidify their intimate contact area with bone. Recent studies have suggested that osteoclast acid secretion is carried out by an H(+)-ATPase. We demonstrate here, that specific inhibitor of vacuolar type H(+)-ATPases, bafilomycin A1, inhibits bone resorption in osteoclast cultures as well as blocks proton transport in isolated medullary bone derived microsomes containing a vacuolar type H(+)-ATPase. These results demonstrate an important role of vacuolar H(+)-ATPase in bone resorption.


Biochimica et Biophysica Acta | 1991

Omeprazole and bafilomycin, two proton pump inhibitors: differentiation of their effects on gastric, kidney and bone H(+)-translocating ATPases.

Jan P. Mattsson; Kalervo Väänänen; Björn Wallmark; Pia Lorentzon

The effects of omeprazole and bafilomycin on processes dependent on two different types of H(+)-translocating ATPases were compared. A H(+)-ATPase of the E1E2-type, the H+,K(+)-ATPase, was purified from gastric mucosa. Vacuolar type H(+)-ATPases were prepared both from kidney medulla and from osteoclast-containing medullary bone. H+,K(+)-ATPase-mediated proton transport in gastric vesicles was selectively inhibited by omeprazole with a high potency (inhibitory concentrations greater than or equal to 3 microM) and in time- and pH-dependent manner. This result is consistent with the mechanism of action of omeprazole, which is dependent on acid-induced transformation of the drug into an active inhibitor reacting with luminally accessible sulfhydryl groups of the enzyme. Accordingly, the presence of the membrane-impermeable mercaptane glutathione did not affect the inhibitory action of omeprazole on the H+,K(+)-ATPase. Proton transport in kidney- and bone-derived membrane vesicles was also inhibited by omeprazole, but with a lower potency (inhibitory concentrations greater than or equal to 100 microM). Furthermore, the presence of glutathione totally abolished this inhibition, indicating that cytosolic, rather than luminal, SH-groups of the respective vacuolar H(+)-ATPase were interacting with omeprazole at high concentrations. In line with these results, it was found that omeprazole was much more potent in inhibiting acid production in isolated gastric glands (IC50 approximately 0.25 microM) than in inhibiting osteoclast-mediated 45Ca-release in isolated mouse calvaria (IC50 approximately 200 microM). Bafilomycin, on the other hand, was much more effective in inhibiting proton transport mediated by the vacuolar H(+)-ATPases in the kidney- and bone-derived membrane vesicles (IC50 approximately 2 nM) than in inhibiting H+,K(+)-ATPase-mediated proton transport in gastric membrane vesicles (IC50 approximately 50 microM). Thus, approximately 10(4) times higher concentrations of bafilomycin were needed to inhibit the H+,K(+)-ATPase to the same extent as the vacuolar H(+)-ATPase. A similar difference in potency of bafilomycin was found when its inhibitory effect was determined in isolated mouse calvaria (IC50 approximately 2.5 nM) and in isolated gastric glands (IC50 approximately 5 microM). Hence, omeprazole was found to be a specific inhibitor of the H+,K(+)-ATPase under physiological conditions, i.e. in the presence of glutathione, while bafilomycin was found to be selective towards vacuolar H(+)-ATPases.


Endocrinology | 2000

Selective estrogenic effects of a novel triphenylethylene compound, FC1271a, on bone, cholesterol level, and reproductive tissues in intact and ovariectomized rats.

Qiang Qu; Huili Zheng; Johanna Dahllund; Aire Laine; Natalia Cockcroft; Zhiqi Peng; Mikko Koskinen; Kari Hemminki; L. Kangas; Kalervo Väänänen; Pirkko Härkönen

FC1271a is a novel triphenylethylene compound with a tissue-selective profile of estrogen agonistic and weak antagonistic effects. It specifically binds to the estrogen receptor alpha and beta with affinity closely similar to that of toremifene and tamoxifen. To study the in vivo effects of the compound, 4-month-old rats were sham operated (sham) or ovariectomized (OVX) and treated daily for 4 weeks with various doses of FC1271a or vehicle (orally). FC1271a was able to oppose OVX-induced bone loss by maintaining the trabecular bone volume of the distal femur. Accordingly, the OVX-induced loss of bone strength was prevented at doses of 1 and 10 mg/kg. FC1271a also prevented the OVX-induced increase in serum cholesterol in a dose-dependent manner. No significant changes in uterine wet weight or morphology were observed in the OVX-rats treated with 0.1 or 1 mg/kg FC1271a, but at a dose of 10 mg/kg it had a slightly estrogenic effect. In immature rats the effect of FC1271a on uterine wet weight was less stimulatory than that of toremifene or tamoxifen, but more stimulatory than that of raloxifene or droloxifene. The appearance of the dimethylbenzanthracene (DMBA)-induced mammary tumors was inhibited by treatment of DMBA-treated rats with FC1271a in a dose-dependent manner. In human MCF-7 breast cancer cell tumors raised in nude mice in the presence of estrogen, the growth and expression of pS2 marker gene could not be maintained after estrogen withdrawal by treatment with FC1271a. No formation of DNA adducts was observed in the liver of the FC1271a-treated rats. In conclusion, the bone-sparing, antitumor, and cholesterol-lowering effects of FC1271a combined with a low uterotropic activity and lack of liver toxicity indicate that FC1271a could be an important alternative in planning antiosteoporosis therapy for estrogen deficiency.


Osteoporosis International | 2003

Lifestyle factors are associated with osteoporosis in lean women but not in normal and overweight women: a population-based cohort study of 1222 women.

Raija Korpelainen; Juha T. Korpelainen; Jorma Heikkinen; Kalervo Väänänen; Sirkka Keinänen-Kiukaanniemi

Abstract The aim of the present population-based cohort study was to evaluate the contribution of lifelong lifestyle factors to calcaneal and distal forearm bone mass in elderly women. We studied 1222 of the 1689 eligible home-dwelling women aged 70–73 years. Lifelong occupational and leisure time physical activity, calcium intake, smoking, alcohol intake and medical history were obtained by a self-completed questionnaire. Main outcome measures were broadband ultrasound attenuation (BUA) of the calcaneus and bone mineral density (BMD) of the radius measured once in 1997–1998. The women with BMI ≤ 25.1 kg m2 had lower BUA (p < 0.0001) and radial BMD values (p < 0.0001) than women with higher BMI. Lifestyle factors associated with BUA in the leanest women were: low physical activity at work (RR 0.4; 95% confidence interval 0.2 to 0.8), low habitual exercise at the ages 30 years , 50 years and currently (RR 1.5; 1.0 to 2.4; RR 1.5; 1.1 to 2.6; RR 1.7; 1.1 to 2.7), poor mobility (RR 1.9; 1.2 to 3.0), coffee intake ≥ 5 cups/day (RR 1.7; 1.1 to 2.7), type 2 diabetes (RR 0.3; 0.1 to 0.9) and hypertension (RR 0.5; 0.3 to 0.8). Type 2 diabetes protected lean women from lower distal and ultradistal radial bone density (RR 0.3; 0.1 to 0.8; RR 0.1; 0.1 to 0.5). The selected lifestyle factors were not associated with lowered calcaneal or radial bone density in the higher categories of BMI. In conclusion, risk factors for lower calcaneal and radial bone density appear to be different among lean and normal/obese women. Lifelong recreational physical activity, low physical activity at work, type 2 diabetes and hypertension seem to be associated with increased bone density, while high coffee intake may increase the risk of lower bone density in lean elderly women. These factors are potentially modifiable, and intervention studies targeted at this risk category of women are needed.


Calcified Tissue International | 2002

Alendronate disturbs vesicular trafficking in osteoclasts.

A. Alakangas; K. Selander; Mika Mulari; Jussi M. Halleen; Petri Lehenkari; J. Mönkkönen; J. Salo; Kalervo Väänänen

The nitrogen-containing bisphosphonate alendronate inhibits osteoclast-mediated bone resorption through inhibition of the mevalonate pathway. This results in impaired protein prenylation and may affect the function of small GTPases in osteoclasts. Since these proteins are important regulators of vesicle transport in cells, we investigated the possible interference of alendronate with these processes in isolated rat osteoclasts. We show here that alendronate-induced inhibition of bone resorption coincides with accumulation of tartrate-resistant acid phosphatase- and electron dense material-containing tubular vesicles in osteoclasts. Alendronate-induced changes in osteoclasts also included widening of the sealing zone areas and incomplete organization of tight attachments and ruffled borders. Osteoclasts also appeared partially detached from the bone surface, and organic matrix was typically dissolved only at the edges of the resorption pits on alendronate-coated bone slices. In contrast, resorption pits on the control and clodronate-coated bone slices were thoroughly resorbed. Inhibition of bone resorption by alendronate was not, however, related to a decrease in osteoclast number. In conclusion, our findings suggest that alendronate inactivates osteoclasts by mechanisms that impair their intracellular vesicle transport, apoptosis being only a secondary phenomenon to this.


Journal of Bone and Mineral Research | 2010

Bone-Resorbing Osteoclasts Contain Gap-Junctional Connexin-43†

Joanna Ilvesaro; Kalervo Väänänen; Juha Tuukkanen

Intercellular gap junctions have been previously described at contact sites between surface osteoblasts, between osteoblasts and underlying osteocytes, and between osteocyte cell processes in the canaliculi. The subunits of gap junction channels are assembled from a family of proteins called connexins. In the present work, we show that rat osteoclasts cultured on bovine bone slices show connexin‐43 (C×43) staining localizing in the plasma membrane of the cells in cell‐cell contacts and over the basolateral membrane of osteoclasts. The effect of heptanol, a known gap‐junctional inhibitor, was studied using the well‐characterized pit formation assay. Heptanol decreased the number and activity of osteoclasts. The proportion of mononuclear tartrate‐resistant acid phosphatase (TRAP)–positive cells out of all TRAP‐positive cells increased on heptanol treatment, suggesting a defect in the fusion of mononuclear osteoclast precursors to multinucleated mature osteoclasts. Furthermore, the total resorbed area and the number of resorption pits also decreased in the heptanol‐treated cultures. These results suggest that gap‐junctional C×43 plays a functional role in osteoclasts and that the blocking of gap junctions decreases both the number and the activity of osteoclasts. This can indicate both a direct communication between multinucleated osteoclasts and mononuclear cells through gap junctions or an indirect effect through gap junctions between osteoblasts. (J Bone Miner Res 2000;15:919–926)


Journal of Bone and Mineral Metabolism | 2006

Effects of ospemifene and raloxifene on biochemical markers of bone turnover in postmenopausal women.

Janne Komi; Kari S. Lankinen; Michael W. DeGregorio; Jorma Heikkinen; Seppo Saarikoski; Marjo Tuppurainen; Kaija Halonen; Risto Lammintausta; Kalervo Väänänen; Olavi Ylikorkala; Risto Erkkola

Ospemifene is a novel selective estrogen receptor modulator (SERM) that is initially being developed for the treatment of vaginal atrophy in postmenopausal women. However, it also shows promise in the prevention and treatment of osteoporosis. As a part of a phase II trial, we compared the effects of ospemifene and raloxifene on bone turnover in postmenopausal women. The study was conducted as a randomized, double-blind study in which 118 healthy postmenopausal women received 30 (n = 29), 60 (n = 30), or 90 mg (n = 30) ospemifene or 60 mg (n = 29) raloxifene for 3 months. Bone resorption was assessed by measuring the urinary outputs of N- and C-terminal cross-linking telopeptides of type I collagen (NTX and CTX, respectively). Bone formation was assessed by measuring bone-specific alkaline phosphatase (bone ALP), osteocalcin (OC), procollagen type I N propeptide (PINP), and procollagen type I C propeptide (PICP) in serum. All markers were studied before and at 3 months and 2–4 weeks after cessation of the medication. Urine NTX outputs decreased in all study groups, and the only statistically significant difference in NTX was observed between raloxifene and 30 mg ospemifene, which was reduced more in the raloxifene group. The output of CTX decreased most clearly in 60- and 90-mg ospemifene groups, but no significant differences between study groups emerged. A significant difference was found between the 90-mg ospemifene group and raloxifene in PINP in favor of ospemifene. No other differences in bone formation markers emerged between ospemifene and raloxifene. The study confirms the bone-restoring activity of ospemifene, which is comparable to that of raloxifene.


Journal of Bone and Mineral Research | 1999

Dietary calcium and bone density in adolescent girls and young women in Europe.

A.F.M. Kardinaal; S. Ando; P. Charles; J. Charzewska; M. Rotily; Kalervo Väänänen; A.M.J. van Erp-Baart; J. Heikkinen; J. Thomsen; M. Maggiolini; A. Deloraine; E. Chabros; R. Juvin; G. Schaafsma

The objective of this study was to investigate the association between dietary calcium intake and radial bone density among young women, over the whole range of intake and at different levels of calcium intake. The study design was a cross‐sectional, observational multicenter investigation in six European countries. One thousand one hundred and sixteen healthy Caucasian girls aged 11–15 years and 526 women aged 20–23 years participated, after having been selected from larger population samples to represent a large range in calcium intake. Bone mineral density (BMD) was measured with dual‐energy X‐ray absorptiometry at the ultradistal and middistal radius. Calcium intake was assessed with 3‐day food records. Other potential determinants of BMD were measured by anthropometry or questionnaires. Mean calcium intake among the girls varied between 609 mg/day in Italy and 1267 mg/day in Finland; intakes for women were in a similar range. After adjustment for height, weight, and age at menarche for the women, and adjustment for age, height, weight, Tanner stage, and bone area for the girls, radial BMD at both sites did not significantly vary among quartiles of calcium intakes for both age groups. In multivariate linear regression, calcium was weakly positively associated with BMD at both sites in the girls (per 100 mg of calcium: β = 0.57 mg/cm2, p = 0.03 for middistal BMD and β = 0.56 mg/cm2, p = 0.01 for ultradistal BMD). For middistal BMD, the association was observed predominantly in premenarcheal girls. The associations were no longer statistically significant after full adjustment for all determinants of BMD, except again in pre‐menarcheal girls. Radial BMD in the women was not associated with calcium intake, except after full adjustment for determinants of BMD, when ultradistal BMD became inversely associated with calcium intake (per 100 mg β = −1.02, p = 0.03); this finding was due to results in one of the countries and not found in other countries. There was no evidence for a different relation between calcium and BMD at different levels of intake; although there was a positive association at calcium intake levels <600 mg/day, the interaction was not significant and there was no consistent trend over intake categories. These results do not support the hypothesis that dietary calcium is a determinant of peak BMD in European women, for a wide range of intake. This study does not provide evidence that Recommended Dietary Allowances for calcium should be increased.


Gene regulation and systems biology | 2008

MicroRNAs Regulate Osteogenesis and Chondrogenesis of Mouse Bone Marrow Stromal Cells

Salla Suomi; Hanna Taipaleenmäki; Anne Seppänen; Tommi Ripatti; Kalervo Väänänen; Teuvo Hentunen; Anna-Marja Säämänen; Tiina Laitala-Leinonen

MicroRNAs (miRNAs) are non-coding RNAs that bind to target mRNA leading to translational arrest or mRNA degradation. To study miRNA-mediated regulation of osteogenesis and chondrogenesis, we compared the expression of 35 miRNAs in osteoblasts and chondroblasts derived from mouse marrow stromal cells (MSCs). Differentiation of MSCs resulted in up- or downregulation of several miRNAs, with miR-199a expression being over 10-fold higher in chondroblasts than in undifferentiated MSCs. In addition, miR-124a was strongly upregulated during chondrogenesis while the expression of miR-96 was substantially suppressed. A systems biological analysis of the potential miRNA target genes and their interaction networks was combined with promoter analysis. These studies link the differentially expressed miRNAs to collagen synthesis and hypoxia, key pathways related to bone and cartilage physiology. The global regulatory networks described here suggest for the first time how miRNAs and transcription factors are capable of fine-tuning the osteogenic and chondrogenic differentiation of mouse MSCs.


Journal of Bone and Mineral Research | 2006

Effect of exercise on extraskeletal risk factors for hip fractures in elderly women with low BMD : A population-based randomized controlled trial

Raija Korpelainen; Sirkka Keinänen-Kiukaanniemi; Jorma Heikkinen; Kalervo Väänänen; Juha T. Korpelainen

We conducted a 30‐month population‐based, randomized, controlled trial in 160 elderly women at risk for fractures on the basis of a low baseline BMD. Mainly home‐based weight‐bearing exercise was effective in improving strength, balance, and gait.

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Sirkku Peltonen

Turku University Hospital

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