OSSA e CALCIO

OSSA & LEGAMENTI

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Gli Omega 3, svolgono un'azione antinfiammatoria ed intervengono nel metabolismo osseo, aumentando l'assorbimento del Calcio e riducendo il riassorbimento osseo (inibizione degli osteoclasti stimolati dalla PGE2, che viene ridotta dagli omega 3)

Altri studi dimostrano un aumento della sintesi del collagene dei legamenti

Ciò porta a delle importanti conseguenze sul trattamento delle malattie degenerative dello scheletro dei denti e dei legamenti.

VitalOil è in grado di elevare le concentrazioni plasmatiche dell'intera famiglia degli Omega 3: ALA, EPA, DHA.

Eur J Med Res. 2003 Aug 20;8(8):381-7.

Dietary fatty acids and immune reactions in synovial tissue.

Adam O.

Walther-Straub Institute, Ludwig-Maximilians-University Munich, Germany. olafadam@Irz.uni-muenchen.de

Inflammation of the synovial membrane in rheumatoid arthritis is mediated by specialized cells necessary for immune response. The most prominent features are the accumulation of mononuclear phagocytes, lymphocytes and leukocytes in the proliferating tissue. Pro-inflammatory and proliferative signals are transmitted to the bone marrow and to the synovial membrane. The result is a monoclonal stimulation of specific cell lines, and synovial proliferation in the inflamed joint. Angiogenesis, synovial hypertrophy, and increased perfusion facilitate the accumulation of inflammatory cells. Components of the autoimmune reaction are described in the international system of classification, the CD-System (cluster of differentiation). Pro-inflammatory signals are mediated by metabolites of arachidonic acid. Prostaglandins, leukotrienes, lipoxines and hydroxy fatty acids, derived from this PUFA, stimulate the formation and the activity of adhesion molecules (integrines), cytokines (gamma-interferon, interleukin-1, interleukin-6, tumor-necrosis factor), chemokines (interleukine-8, macrophage-chemotactic peptide, RANTES and colony -stimulating factors ((CSF, granulocytes/ monocytes-CSF, Multi-CSF (= IL-3)). Dietary means to mitigate inflammation comprise reduction of arachidonic acid, and increased intake of eicosapentaenoic acid and antioxidants. In the literature 12 randomized, placebo-controlled double-blind studies, fulfilling GCP-criteria, demonstrate a moderate but consistent improvement of clinical findings and laboratory parameters in patients with RA. A dose-response relationship was established up to an daily dose of 2.6 gram fish oil, equivalent to about 1.6 gram EPA. In these experiments EPA was the omega-3 fatty acid responsible for improvement, with distinct effects on inhibition of cytokines formation (IL-1 to IL-6, IL-8, TFN-alpha, GM-CSF), decreased induction of proinflammatory adhesion molecules (selectines, intercellular adhesions molecule-1 (ICAM-1)), and degrading enzymes (e.g. phospholipase A2, cyclooxygenase-2, inducible NO-synthetase). Only one study reports the relevance of the background diet. From this study it became apparent that reduction of dietary arachidonic acid improves the incorporation and the clinical benefit of EPA.

J Hum Nutr Diet. 2003 Apr;16(2):97-109.

Nutritional management of rheumatoid arthritis: a review of the evidence.

Rennie KL, Hughes J, Lang R, Jebb SA.

MRC Human Nutrition Research, Elsie Widdowson Laboratory, Fulbourn Road, Cambridge, UK. kirsten.rennie@mrc-hnr.cam.ac.uk

Rheumatoid arthritis (RA) is a debilitating disease and is associated with increased risk of cardiovascular disease and osteoporosis. Poor nutrient status in RA patients has been reported and some drug therapies, such as nonsteroidal anti-inflammatory drugs (NSAIDs), prescribed to alleviate RA symptoms, may increase the requirement for some nutrients and reduce their absorption. This paper reviews the scientific evidence for the role of diet and nutrient supplementation in the management of RA, by alleviating symptoms, decreasing progression of the disease or by reducing the reliance on, or combating the side-effects of, NSAIDs. Supplementation with long-chain n-3 polyunsaturated fatty acids (PUFA) consistently demonstrates an improvement in symptoms and a reduction in NSAID usage. Evidence relating to other fatty acids, antioxidants, zinc, iron, folate, other B vitamins, calcium, vitamin D and fluoride are also considered. The present evidence suggests that RA patients should consume a balanced diet rich in long-chain n-3 PUFA and antioxidants. More randomized long-term studies are needed to provide evidence for the benefits of specific nutritional supplementation and to determine optimum intake, particularly for n-3 PUFA and antioxidants.

Maturitas. 2002 May 20;42(1):13-22.

Polyunsaturated fatty acids. Is there a role in postmenopausal osteoporosis prevention?

Albertazzi P, Coupland K.

Centre for Metabolic Bone Disease, H. S Brocklehurst Building, Hull Royal Infirmary, 220-236 Anlaby Road, Hull, UK. p.albertazzi@medschool.hull.ac.uk

OBJECTIVE: To review the effect of a diet supplemented with polyunsaturated fatty acids (PUFA) on prevention or treatment of osteoporosis. METHODS: MEDLINE (1966-April 2001), Allied Complementary Medicine (1985-2001), Cochrane Library and Database of Systematic Reviews (1st Quarter 2001) was searched. Five reviews and no systematic reviews were found on this topic in the Cochrane Library. Eleven relevant in-vivo studies were identified on the effect of these compounds on bone. Eight were animal studies and three were randomised control trials (RCT) in human.

RESULTS: There are two classes of PUFA designated as n-3 and n-6 with alpha-linolenic acid (ALA). These two different types of PUFA differently influence prostaglandin formation and hence modulate bone metabolism differently. These are several in vitro and animal data suggesting that diet with a low n-6/n-3 ratio may have beneficial effects on bone mineral density. Only three, short-term, small studies have been performed in human so far. Two studies, one performed with bone markers and one with bone density showed a positive effect of PUFA on bone. While a third study showed no effect.

CONCLUSIONS: Preliminary, data have suggested that a diet with a low n-6/n-3 ratio may have beneficial effects on bone mineral density. Further studies are, however, required to fully assess the dose and type of PUFA to be used for optimum bone effects. This may be useful particularly for the prevention of disease in the elderly, since a diet rich in n-3 PUFA has been shown to have additional benefit on the cardiovascular, central nervous system and joints.

Aging (Milano). 1998 Oct;10(5):385-94.

Calcium, gamma-linolenic acid and eicosapentaenoic acid supplementation in senile osteoporosis.

Kruger MC, Coetzer H, de Winter R, Gericke G, van Papendorp DH.

Department of Physiology, University of Pretoria, South Africa.

Recent animal work suggests that gamma-linolenic acid (GLA) and eicosapentaenoic acid (EPA) enhance calcium absorption, reduce excretion and increase calcium deposition in bone. A pilot study was set up to test the interactions between calcium and GLA + EPA in humans. Sixty-five women (mean age 79.5), taking a background diet low in calcium, were randomly assigned to GLA + EPA or coconut oil placebo capsules; in addition, all received 600 mg/day calcium as the carbonate. Markers of bone formation/degradation and bone mineral density (BMD) were measured at baseline, 6, 12 and 18 months. Twenty-one patients were continued on treatment for a second period of 18 months, after which BMD (36 months) was measured. At 18 months, osteocalcin and deoxypyridinoline levels fell significantly in both groups, indicating a decrease in bone turnover, whereas bone specific alkaline phosphatase rose indicating beneficial effects of calcium given to all the patients. Lumbar and femoral BMD, in contrast, showed different effects in the two groups. Over the first 18 months, lumbar spine density remained the same in the treatment group, but decreased 3.2% in the placebo group. Femoral bone density increased 1.3% in the treatment group, but decreased 2.1% in the placebo group. During the second period of 18 months with all patients now on active treatment, lumbar spine density increased 3.1% in patients who remained on active treatment, and 2.3% in patients who switched from placebo to active treatment; femoral BMD in the latter group showed an increase of 4.7%. This pilot controlled study suggests that GLA and EPA have beneficial effects on bone in this group of elderly patients, and that they are safe to administer for prolonged periods of time.

J Nephrol. 2002 Nov-Dec;15(6):601-4.

Fatty acids, calcium and bone metabolism.

Baggio B.

Department of Medical-Surgical Sciences, University of Padova, Italy. bruno.baggio@unipd.it

Epidemiological, clinical and experimental evidence suggests that fatty acids may have an effect (due to their chemical structure) on calcium metabolism in animals and man. Fatty acid deficiency in animals can lead to a loss of bone calcium and matrix, resulting in marked bone demineralization, and treatment with a mixture of omega-3 and omega-6 polyunsaturated fatty acids can induce significant reduction in some biochemical markers of bone reabsorption. A relationship, between phospholipid fatty acid content, calcium-regulating hormones and intestinal, renal, and bone calcium metabolism alterations, has been reported in patients with renal stones and hypercalciuria. Recent studies have shown specific effects of fatty acids on the gene expression of some bone cytokines. Fatty acids might be involved in calcium metabolism influencing cellular calcium ion transport directly, as second messengers, or generating, through the cyclooxygenase pathway, potential biological mediators which have complex effects on bone remodeling. Experimental and clinical documentation of the specific and indirect effects of fatty acids on calcium and bone metabolism could open up new and interesting clinical prospects.

Prostaglandins Leukot Essent Fatty Acids. 2003 Jun;68(6):423-9.

Omega-3 fatty acids modulate ATPases involved in duodenal Ca absorption.

Haag M, Magada ON, Claassen N, Bohmer LH, Kruger MC.

Department of Physiology, University of Pretoria, PO Box 2034, Pretoria 0001, South Africa. mhaag@medic.up.ac.za

Dietary supplementation with fish oil that contains omega-3 polyunsaturated fatty acids has been shown to enhance bone density as well as duodenal calcium uptake in rats. The latter process is supported by membrane ATPases.

The present in vitro study was undertaken to test the effect of omega-3 fatty acids on ATPase activity in isolated basolateral membranes from rat duodenal enterocytes. Ca-ATPase in calmodulin-stripped membranes was activated in a biphasic manner by docosahexanoic acid (DHA) (10-30 microg/ml) but not by eicosapentanoic acid (EPA). This effect was blocked partially by 0.5 microM calphostin (a protein kinase C blocker). DHA inhibited Na,K-ATPase (-49% of basal activity, [DHA]=30 microg/ml, P <0.01). This effect could be reversed partially by 50 microM genistein, a tyrosine kinase blocker. EPA also inhibited Na,K-ATPase: (-47% of basal activity, [EPA]=30 microg/ml, P <0.01), this effect was partially reversed by 100 microM indomethacin, a cyclo-oxygenase blocker. Omega-3 fatty acids are thus involved in multiple signalling effects that effect ATPases in BLM.

J Nutr. 2002 Sep;132(9):2667-72.

Modulation of essential (n-6):(n-3) fatty acid ratios alters fatty acid status but not bone mass in piglets.

Weiler HA, Fitzpatrick-Wong SC.

Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, Manitoba R3T 2N2 Canada. hweiler@ms.umanitoba.ca

Dietary (n-6) and (n-3) fatty acids have been implicated as important regulators of bone metabolism. The main objective of this research was to define the response of whole-body growth, fatty acid status and bone mass to a reduced dietary (n-6):(n-3) fatty acid ratio. A secondary objective was to determine whether there is an amount of fat x fatty acid ratio interaction for these outcomes. Piglets (n = 32) were randomized to 1 of 4 diets: group 1: [30 g fat/L + (n-6):(n-3) ratio 4.5:1]; group 2: [30 g fat/L + (n-6):(n-3) ratio 9.0:1]; group 3: [60 g fat/L + (n-6):(n-3) ratio 4.5:1]; and group 4: [60 g fat/L + (n-6):(n-3) ratio 9.0:1]. After 21 d, outcomes assessed included growth, fatty acid status and bone mass and metabolism. Growth and bone mass did not differ among the four groups nor did arachidonic acid (AA as g/100 g fatty acids) in plasma, adipose and brain. Piglets fed diets 1 and 3 with the lower (n-6):(n-3) ratio had lower liver AA (P < 0.001). Those fed diets 1 and 2 containing 30 g fat/L had lower docosahexaenoic acid (DHA as g/100 g fatty acids) in liver (P < 0.001), plasma (P = 0.019) and adipose tissue (P = 0.045). However, piglets fed diets 1 and 3 had higher (P < 0.001) brain DHA than those fed diets with a higher (n-6):(n-3) ratio. Higher plasma DHA was associated with less bone resorption (r = -0.44, P = 0.01). Therefore, elevation of dietary (n-3) fatty acids supports growth and fatty acid status while not compromising bone mass. The results may be of relevance to the nutritional management of preterm infants whose DHA status is often too low and bone resorption too high.

Clin Sci (Lond). 2002 Apr;102(4):403-9.

Fatty acids and cytokine mRNA expression in human osteoblastic cells: a specific effect of arachidonic acid.

Priante G, Bordin L, Musacchio E, Clari G, Baggio B.Department of Medical-Surgical Sciences, University of Padova, Via Giustiniani 2, 35128 Padua, Italy.

Epidemiological, clinical and experimental evidence suggests that fatty acids have a modulatory effect on bone metabolism in animals and humans. To investigate this hypothesis, we evaluated the effects of three different fatty acids, arachidonic acid (AA), eicosapentaenoic acid (EPA) and oleic acid (OA), on the expression of cytokines involved in bone remodelling. Cytokine mRNAs in the human osteoblast-like cell line MG-63 were quantified by reverse transcription-PCR. AA induced increased expression of interleukin-1alpha, interleukin-1beta, tumour necrosis factor-alpha and macrophage colony-stimulating factor mRNAs in a time- and dose-dependent manner. EPA and OA had no stimulatory effects, but instead caused a significant inhibition of AA-induced cytokine mRNA expression. Cell treatment with calphostin C, an inhibitor of protein kinase C (PKC), and cellular PKC down-regulation experiments independently resulted in significant inhibition of AA-induced cytokine expression, suggesting that a PKC-dependent mechanism accounts for the effects of AA on cytokine production. In conclusion, our study demonstrates specific effects of fatty acids on cytokine gene expression in human osteoblast-like cells. The clinical relevance of our findings requires further investigation.

Exp Biol Med (Maywood). 2001 Jun;226(6):485-97.

Omega-3 polyunsaturated fatty acids and skeletal health.

Watkins BA, Li Y, Lippman HE, Seifert MF.

Department of Food Science, Lipid Chemistry and Molecular Biology Laboratory, Purdue University, West Lafayette, Indiana 47907, USA. watkins@foodsci.purdue.edu

This minireview on skeletal biology describes the actions of prostaglandins and cytokines involved in the local regulation of bone metabolism, it documents the role of lipids in bone biology, and it presents relationships between fatty acids and other factors that impact skeletal metabolism. The data presented herein show consistent and reproducible beneficial effects of omega-3 (n-3) fatty acids on bone metabolism and bone/joint diseases. Polyunsaturated fatty acids modulate eicosanoid biosynthesis in numerous tissues and cell types, alter signal transduction, and influence gene expression. These effects have not been explored in the skeletal system. Future research on n-3 fatty acids in bone biology should focus on the following two aspects. First, the further elucidation of how n-3 fatty acids alter biochemical and molecular processes involved in bone modeling and bone cell differentiation, and second, the evaluation of the potential pharmaceutical applications of these nutraceutical fatty acids in maintaining bone mineral status and controlling inflammatory bone/joint diseases.

Altern Med Rev. 2001 Feb;6(1):61-77.

Can manipulation of the ratios of essential fatty acids slow the rapid rate of postmenopausal bone loss?

Kettler DB.

Sky Park Wellness Center, Irvine, CA 92614, USA dr.debra@home.com

The rapid rate of postmenopausal bone loss is mediated by the inflammatory cytokines interleukin-1, interleukin-6, and tumor necrosis factor alpha. Dietary supplementation with fish oil, flaxseeds, and flaxseed oil in animals and healthy humans significantly reduces cytokine production while concomitantly increasing calcium absorption, bone calcium, and bone density. Possibilities may exist for the therapeutic use of the omega-3 fatty acids, as supplements or in the diet, to blunt the increase of the inflammatory bone resorbing cytokines produced in the early postmenopausal years, in order to slow the rapid rate of postmenopausal bone loss. Evidence also points to the possible benefit of gamma-linolenic acid in preserving bone density.

Prog Lipid Res. 2001 Jan-Mar;40(1-2):125-48.

Bioactive fatty acids: role in bone biology and bone cell function.

Watkins BA, Lippman HE, Le Bouteiller L, Li Y, Seifert MF.

Department of Food Science, Lipid Chemistry and Molecular Biology Laboratory, Purdue University, 47907, West Lafayette, IN, USA

Bone is a unique tissue providing support, movement, and mineral balance for the body. Bone growth is achieved in the young by a process called modeling, and maintained during adulthood by a process termed remodeling. Three types of cells are responsible for the formation of cartilage and bone; the chondrocyte, osteoblast, and osteoclast. These cells are under the influence of a plethora of regulatory molecules, which govern their action to provide an individual optimal bone mass. Interruption of this homeostatic machinery, especially in the elderly, often results in a loss of bone mass (osteoporosis) or cartilage damage (rheumatoid arthritis). Many pharmacological agents have been made available in an effort to prevent or alleviate these pathologies, however, one vector often overlooked is the diet. This review focuses on the relationship between dietary polyunsaturated fatty acids and bone biology, both in vivo and in vitro.

J Cell Biochem. 2003 Oct 1;90(2):347-60.

Effects of long-term administration of N-3 polyunsaturated fatty acids (PUFA) and selective estrogen receptor modulator (SERM) derivatives in ovariectomized (OVX) mice.

Zeitlin L, Segev E, Fried A, Wientroub S.

Department of Pediatric Orthopaedics, Dana Children's Hospital, Tel Aviv Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Israel.

We studied the beneficial effects of dietary consumption of n-3 polyunsaturated fatty acids (PUFA) and two selective estrogen receptor modulator (SERM) derivatives (SERM-I and SERM-II) and their combined effect on serum lipids, skin dermis and adipose layers, bone marrow adipogenesis, and cytokine secretion in mice. Two different ovariectomized (OVX) models were studied: treatment began immediately post-OVX in one and 3 months post-OVX in the other. Our results showed that n-3 PUFA and both SERMs decreased triglyceride levels in the serum, and that SERMs also decreased serum cholesterol levels while n-3 PUFA had no similar effect. SERMs had no effect on IL-6, IL-1 beta, or IL-10 levels, but they decreased ex vivo tumor necrosis factor (TNF-alpha). N-3 PUFA decreased secretion of non-induced IL-6 and TNF-alpha from cultured BMC and IL-1 beta levels in vivo (i.e., in bone marrow plasma), but its main effect was a significant elevation in the secretion of IL-10, a known anti-inflammatory cytokine. OVX-induced B-lymphopoiesis was not affected by LY-139481 (SERM-I) while LY-353381 (SERM-II) exhibited an estrogen-antagonistic effect in sham and OVX mice and elevated the amount of B-cells in bone marrow. Fish oil consumption prevented the elevation in B-lymphopoiesis caused by OVX, but had no curative effect on established augmented B-lymphopoiesis. This activity could be mediated via the elevation of IL-10 which was shown to suppress B-lymphopoiesis. Both SERMs and n-3 PUFA inhibited the increase in adipose tissue thickness caused by OVX in mice. Our results showed that n-3 PUFA, could prevent some of the deleterious outcomes of estrogen deficiency that were not affected by SERMs. We observed no significant beneficial effects of the combined administration of SERM-I, SERM-II, and PUFA on the studied parameters.The exact mechanism by which polyunsaturated fatty acids exert their activities is still not clear, but peroxisome proliferator-activated receptors (PPARs) might be involved in processes which are modulated by n-3 PUFA. J. Cell. Biochem. 90: 347-360, 2003. Copyright 2003 Wiley-Liss, Inc

J Nutr. 2000 Sep;130(9):2274-84.

Dietary ratio of (n-6)/(n-3) polyunsaturated fatty acids alters the fatty acid composition of bone compartments and biomarkers of bone formation in rats.

Watkins BA, Li Y, Allen KG, Hoffmann WE, Seifert MF.

Department of Food Science, Lipid Chemistry and Molecular Biology Laboratory, Purdue University, West Lafayette, IN 47907, USA.

The effects of dietary polyunsaturated fatty acids (PUFA) on ex vivo bone prostaglandin E(2) (PGE(2)) production and bone formation rate were evaluated in rats. Weanling male Sprague-Dawley rats were fed AIN-93G diet containing 70 g/kg of added fat for 42 d. The dietary lipid treatments were formulated with safflower oil and menhaden oil to provide the following ratios of (n-6)/(n-3) fatty acids: 23.8 (SMI), 9.8 (SMII), 2.6 (SMIII), and 1.2 (SMIV). Ex vivo PGE(2) production in liver homogenates and bone organ cultures (right femur and tibia) were significantly lower in rats fed diets with a lower dietary ratio of (n-6)/(n-3) fatty acids than in those fed diets with a higher dietary ratio. Regression analysis revealed a significant positive correlation between bone PGE(2) and the ratio of arachidonic acid (AA)/eicosapentaenoic acid (EPA), but significant negative correlations between bone formation rate and either the ratio of AA/EPA or PGE(2) in bone. Activities of serum alkaline phosphatase isoenzymes, including the bone-specific isoenzyme (BALP), were greater in rats fed a diet high in (n-3) or a low ratio of (n-6)/(n-3), further supporting the positive action of (n-3) fatty acids on bone formation. These results demonstrated that the dietary ratio of (n-6)/(n-3) modulates bone PGE(2) production and the activity of serum BALP in growing rats.

Clin Nutr. 2000 Aug;19(4):271-6.

Serum fatty acid imbalance in bone loss: example with periodontal disease.

Requirand P, Gibert P, Tramini P, Cristol JP, Descomps B.

Faculty of Dentistry of Montpellier, Institute of Biology, Montpellier, France.

Among the numerous factors of bone remodelling, the local action of arachidonic acid metabolites together with cytokines, is particularly important, especially that of prostaglandin PGE2. It has been suggested that the alveolar bone destruction in periodontal disease and osteoporosis can be treated by reducing the ratio of arachidonic acid in phospholipids, which would diminish prostaglandin production. The aim of this study was to evaluate the main serum polyunsaturated fatty acids and a possible alteration in the level of arachidonic acid in patients suffering from periodontal bone loss. Of the 105 patients who participated the study, 78 were suffering from periodontal bone loss and 27 served as a control group. The fatty acids were measured in serum by gas-chromatography. The results showed that the level of fatty acids of the n-6 pathway was higher in our patients with bone loss than in the control group, whereas the reverse was observed with fatty acids of the n-3 pathway. In conclusion, our patients' bone losses are linked with an imbalance between n-6 and n-3 fatty acids, which seems to justify a diet increase in 20- and 22-carbon fatty acids. Copyright 2000 Harcourt Publishers Ltd.

Proc Soc Exp Biol Med. 2000 Jan;223(1):88-95.

Omega-3 fatty acids enhance ligament fibroblast collagen formation in association with changes in interleukin-6 production.

Hankenson KD, Watkins BA, Schoenlein IA, Allen KG, Turek JJ.

Department of Basic Medical Sciences, Lipid Chemistry Laboratory, Purdue University, West Lafayette, Indiana 47907, USA.

Altering dietary ratios of n-3 and n-6 polyunsaturated fatty acids (PUFA) represents an effective nonpharmaceutical means to improve systemic inflammatory conditions. An effect of PUFA on cartilage and bone formation has been demonstrated, and the purpose of this study was to determine the potential of PUFA modulation to improve ligament healing. The effects of n-3 and n-6 PUFA on the in vitro healing response of medial collateral ligament (MCL) fibroblasts were investigated by studying the cellular coverage of an in vitro wound and the production of collagen, PGE2, IL-1, IL-6, and TNF. Cells were exposed to a bovine serum albumin (BSA) control or either eicosapentaenoic acid (EPA, 20:5n-3) or arachidonic acid (AA, 20:4n-6) in the form of soaps loaded onto BSA for 4 days and wounded on Day 5. AA and EPA improved the healing of an in vitro wound over 72 hr. EPA increased collagen synthesis and the overall percentage of collagen produced, but AA reduced collagen production and total protein. PGE2 production was increased in the AA-treated group and decreased in the EPA-treated group, but was not affected by wounding. IL-1 was not produced at the time point evaluated, but TNF and IL-6 were both produced, and their levels varied relative to the PUFA or wounding treatment. There was a significant linear correlation (r2 = 0.57, P = 0.0045) between IL-6 level and collagen production. These results demonstrate that n-3 PUFA (represented by EPA in this study) positively affect the healing characteristics of MCL cells and therefore may represent a possible noninvasive treatment to improve ligament healing. Additionally, these results show that MCL fibroblasts produce PGE2, IL-6, and TNF and that IL-6 production is related to MCL collagen synthesis.

Angle Orthod. 1999 Aug;69(4):365-71.

Influence of dietary n-3 polyunsaturated fatty acid on experimental tooth movement in rats.

Iwami-Morimoto Y, Yamaguchi K, Tanne K.

Department of Orthodontics, Hiroshima University, School of Dentistry, Japan. yiwami@ipc.hiroshima-u.ac.jp

This study was conducted to investigate the influence of dietary n-3 polyunsaturated fatty acid on experimental tooth movement. This acid substantially reduces the production of arachidonic acid. Sixty 4-week-old male Wistar strain rats were divided into experimental and control groups. Animals in the experimental group were fed a purified diet containing 10% refined fish oil (rich in n-3 fatty acid); control animals were fed a diet containing 10% corn oil (rich in n-6 fatty acid). After 6 weeks, the maxillary first molars were moved buccally with an initial force of 20 g for periods of 0, 3, 7, or 14 days. Tooth movement in the experimental group was 80% of that seen in the controls. The number of osteoclasts on the pressure side during tooth movement was nearly 60% of that seen in controls, and the degree of bone resorption was 80%. The data suggest that a diet enriched with fish oil reduces osteoclastic activity and subsequent alveolar bone resorption that is the key to experimental tooth movement.

Aging (Milano). 1998 Oct;10(5):385-94.

Calcium, gamma-linolenic acid and eicosapentaenoic acid supplementation in senile osteoporosis.

Kruger MC, Coetzer H, de Winter R, Gericke G, van Papendorp DH.

Department of Physiology, University of Pretoria, South Africa.

Lipids. 1997 Mar;32(3):293-302.

Incorporation of long-chain n-3 fatty acids in tissues and enhanced bone marrow cellularity with docosahexaenoic acid feeding in post-weanling Fischer 344 rats.

Atkinson TG, Barker HJ, Meckling-Gill KA.

Department of Human Biology and Nutritional Sciences, University of Guelph, Ontario, Canada.

We wanted to examine the effects of an oil rich in docosahexaenoic acid (DHA), without eicosapentaenoic acid, on the composition of membrane phospholipid in a variety of tissues. Our in vitro studies had previously shown that DHA could modify glucose and nucleoside transport in cells in culture and also increase selectivity of the nucleoside drug, arabinosylcytosine (araC) toward tumor cells. Here we wanted to examine what effect DHA supplementation would have in the whole animal in terms of the chemosensitivity of normal bone marrow, the dose-limiting tissue during chemotherapy, to araC. The purpose was to determine whether fatty acid supplementation might be useful as an adjuvant to chemotherapy. We fed diets containing 5% (w/w) low fat-corn oil (LF-CO group), 10% moderate fat-safflower oil (MF-SO group), or 10% DHASCO (MF-DHA group) to weanling Fischer 344 rats for 8-9 wk. Feed intake and growth were not different between the different diets. Similarly, treatment of animals with the chemotherapeutic drug araC did not differentially affect growth, feed intake, or tissue fatty acid composition for the different diet groups. Fatty acid compositions of bone marrow, liver, red blood cells, plasma phospholipid and triglyceride, as well as skeletal and cardiac muscle, were substantially different between the dietary groups. The DHASCO oil contained 46% DHA (22:6n-3) and resulted in profound incorporation of DHA in all tissues examined. The most dramatic response was seen in skeletal muscle of MF-DHA fed animals where DHA represented 46% of membrane phospholipid fatty acids. This is likely to have consequences to muscle function. Although DHASCO contains a similar level of saturated fatty acids (42%), few differences in saturates were noted between the various dietary groups for most of the tissues examined. Both LF-CO and MF-SO diets were hypercholesterolemic, and the LF-CO was also hypertriglyceridemic compared to the chow-fed animals. Animals fed the MF-DHA diet had the lowest triglyceride levels of any of the treatment groups and cholesterol levels comparable to chow-fed animals. MF-DHA had substantially higher numbers of colony-forming units-granulocyte macrophage (CFU-GM) as reflected in a twofold higher bone marrow cellularity than either chow or LF-CO animals, suggesting expansion of the bone marrow compartment with DHA feeding. Although higher than LF-SO, the number of CFU-GM in MF-SO animals was not significantly higher than animals fed chow. Bone marrow from LF-CO animals appeared to be more resistant to araC treatment than either MF group. Thus, DHA, fed as DHASCO, has advantages over low or moderate n-6 diets and chow as it is has both hypolipidemic- and bone marrow-enhancing properties in weanling Fischer 344 rats. This suggests that DHA supplementation may be useful in adjuvant chemotherapy.

Diabetes Res Clin Pract. 1995 Oct;30(1):37-42.

Effect of eicosapentaenoic acid and docosahexaenoic acid on diabetic osteopenia.

Yamada Y, Fushimi H, Inoue T, Matsuyama Y, Kameyama M, Minami T, Okazaki Y, Noguchi Y, Kasama T.

Department of Internal Medicine, Sumitomo Hospital, Osaka, Japan.

To evaluate the effect of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are polyunsaturated fatty acids, on diabetic osteopenia, we measured the bone fragility in streptozotocin-induced diabetic rats. The fragility of femur was increased in diabetic rats, which was prevented in part by EPA or DHA. Moreover, EPA prevented osteopenia even in diabetic rats fed a low zinc feed, which was a potent accelerator of diabetic osteopenia. Plasma alkaline phosphatase activity and parathyroid hormone level showed no difference between the two groups of diabetic rats with or without EPA. Urinary excretion of calcium and phosphate was increased and plasma inorganic phosphate level was high in diabetic rats, suggesting severe mineral loss. In diabetic rats fed EPA, although urinary and plasma calcium levels did not change significantly, urinary phosphate excretion and plasma inorganic phosphate concentration were slightly lowered, which suggested that EPA may have an effect in suppressing phosphate release from bones in diabetic rats. These data suggest that EPA and DHA could be effective on diabetic osteopenia, but to elucidate the precise mechanisms, further examinations will be needed.

Prostaglandins Leukot Essent Fatty Acids. 1995 Jul;53(1):13-9.

The effect of different n-6/n-3 essential fatty acid ratios on calcium balance and bone in rats.

Claassen N, Coetzer H, Steinmann CM, Kruger MC.

Department of Physiology, Faculty of Medicine, University of Pretoria, South Africa.

Prostaglandins (PGs) are known to have various effects on bone metabolism. The supplementation of essential fatty acids (EFAs), the precursors of PGs, leads to increased intestinal calcium absorption and calcium balance. It is, however, not known whether increased calcium absorption and calcium balance will enhance the calcium content in bone. Male Sprague-Dawley rats (n = 40) aged 5-12 weeks were supplemented with EFAs. The main dietary EFAs, linoleic acid (LA) and alpha-linolenic acid (ALA) were administered in a ratio of 3:1 as a control group. The conversion of LA to ALA to the PG precursors is slow, with the first step, delta-6-desaturation being rate limiting. Fatty acids beyond this rate-limiting step, gamma-linolenic acid (GLA, n-6) and eicoapentaenioc acid (EPA, n-3), were administered to different groups in the ratios 3:1, 1:1 and 1:3 to explore the impact of different ratios of n-6 and n-3 EFAs. Intestinal calcium absorption (mg/24 h) increased by 41.5% in the 3:1 supplemented group, compared with the control group. The decrease in urinary calcium (mg/24 h) correlated with the increase in n-3 level. The calcium balance (mg/24 h) and bone calcium (mg/g bone ash) increased significantly in the 3:1 (41.5% and 24.7%) group, compared with the control. The increase in bone calcium might be attributed to an EFA-induced increase in circulating PGs. An increased synthesis of PGs acting on target bone cells, as well as changes in membrane fluidity, may underlie these observations

Bone. 1995 Apr;16(4 Suppl):385S-392S.

Supplemented gamma-linolenic acid and eicosapentaenoic acid influence bone status in young male rats: effects on free urinary collagen crosslinks, total urinary hydroxyproline, and bone calcium content.

Claassen N, Potgieter HC, Seppa M, Vermaak WJ, Coetzer H, Van Papendorp DH, Kruger MC.

Department of Physiology, Faculty of Medicine, University of Pretoria, Republic of South Africa.

The effect of different ratios of the prostaglandin precursors gamma-linolenic (GLA) and eicosapentaenoic (EPA) acids on bone status in growing rats measured as a function of free urinary pyridinium crosslinks and hydroxyproline levels was investigated. Male Sprague-Dawley rats were weaned onto an essential fatty acid deficient diet and from their fifth week, different groups of rats received a balanced, semisynthetic diet, supplemented with different ratios of GLA:EPA supplied as a mixture of evening primrose oil (EPO) and fish oil (FO). Controls were supplemented with linoleic (LA; sunflower oil) and alpha-linolenic (ALA; linseed oil) acids (3:1) or a commercially available rat chow. Animals were terminated at 84 days and femur length, ash weight, calcium content, free urinary pyridinium crosslinks (Pyd and Dpyd), total hydroxyproline (Hyp), and creatinine levels measured. Free urinary Pyd and Dpyd are good indicators of bone status and they correlated well with Hyp. Pyd and Dpyd excretion were significantly decreased in the higher GLA:EPA dietary groups and correlated well (r = 0.7) with Hyp levels. Concomitantly, bone calcium content increased significantly in the same dietary groups. These results suggest that diet supplementation with relatively high GLA:EPA ratios are more effective in inhibiting bone resorption than LA:ALA.

Prostaglandins Leukot Essent Fatty Acids. 1994 Feb;50(2):81-4.

Eicosapentaenoic acid inhibits bone loss due to ovariectomy in rats.

Sakaguchi K, Morita I, Murota S.

Section of Physiological Chemistry, Graduate School, Tokyo Medical and Dental University, Japan.

Eicosapentaenoic acid (EPA), one of the polyunsaturated fatty acids, is well-known to have a wide variety of beneficial biological functions. In the present work we demonstrate another new beneficial effect of EPA on bone metabolism in vivo. Ovariectomized rats were divided into 4 groups under the same calorie intake condition; (1) normal diet, (2) low calcium diet (1.5 mg/day), (3) EPA-enriched diet (160 mg/day/kg), (4) EPA-enriched and low calcium diet. These diets were continued for 35 consecutive days. The bone weight of the femora and tibiae decreased significantly in the low calcium group, but the decrease was inhibited in the EPA-low calcium group. Moreover, in the rupture test, which indicates bone strength, the femora in the low calcium group were easier to break than in the normal calcium diet groups. In the EPA-low calcium group the strength of the bone was equivalent to that in the normal diet group. These results suggest that an EPA-enriched diet prevents the loss of bone weight and strength caused by oestrogen deficiency or inadequate nutrition. There is a possibility that EPA could be developed to be a novel anti-osteoporosis drug.

Modulatory effect of omega-3 polyunsaturated fatty acids on osteoblast function and bone metabolism.

Watkins BA, Li Y, Lippman HE, Feng S.

Center for Enhancing Foods to Protect Health, Lipid Chemistry and Molecular Biology Laboratory, Department of Food Science, Purdue University, 745 Agriculture Mall Drive, West Lafayette, IN 47907, USA. baw@purdue.edu

Recent investigations indicate that the type and amount of polyunsaturated fatty acids (PUFA) influence bone formation in animal models and osteoblastic cell functions in culture. In growing rats, supplementing the diet with omega-3 PUFA results in greater bone formation rates and moderates ex vivo prostaglandin E(2) production in bone organ cultures. A protective effect of omega-3 PUFA on minimizing bone mineral loss in ovariectomized rats has also been reported. The actions of omega-3 fatty acids on bone formation appear to be linked to altering osteoblast functions. Herein we describe experiments with MC3T3-E1 osteoblast-like cells that support findings in vivo where omega-3 PUFA modulated COX-2 protein expression, reduced prostaglandin E(2) production, and increased alkaline phosphatase activity. Other studies indicate that the dietary source of PUFA may affect protein expression of Cbfa1 and nodule formation in fetal rat calvarial cells.

Biochem Biophys Res Commun. 2003 Jan 24;300(4):957-64.

Role of prostaglandin E produced by osteoblasts in osteolysis due to bone metastasis.

Ohshiba T, Miyaura C, Ito A.

Department of Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432 Horinouchi, Hachioji, Tokyo 192-0392, Japan.

Prostaglandin E2 (PGE2) is produced in bone mainly by osteoblasts and stimulates bone resorption. Osteolytic bone metastasis of cancers is accompanied by bone resorption. In this study, we examined the roles of PGE2 in osteolysis due to bone metastasis of breast cancer. Injection of human breast cancer cells, MDA-MB-231 (MDA-231), into nude mice causes severe osteolysis in the femur and tibia. The expression of cyclo-oxygenase-2 (COX-2) and the receptor activator of NF-kappaB ligand (RANKL), a key molecule in osteoclast differentiation, mRNAs was markedly elevated in bone with metastasis. When MDA-231 cells were cocultured with mouse calvaria, COX-2-induced PGE2 production and bone resorption progressed. The contact with MDA-231 cells could induce the expression of COX-2 and RANKL in osteoblasts by mechanisms involving MAP kinase and NF-kappaB. The blockage of PGE2 signal by indomethacin and EP4 antagonist abrogated the osteoclast formation induced by the breast cancer cells. Here, we show a PGE-dependent mechanism of osteolysis due to bone metastasis.

Prostaglandins. 1989 May;37(5):615-25.

Effects of prostaglandin E3 and eicosapentaenoic acid on rat bone in organ culture.

Raisz LG, Alander CB, Simmons HA.

Division of Endocrinology and Metabolism, University of Connecticut Health Center, Farmington 06032.

To assess the possibility that diets rich in eicosapentaenoic acid (EPA) could have adverse effects on the skeleton, we examined the resorptive response to its major project, PGE3, and the effects and metabolism of EPA itself in cultured fetal rat long bones and neonatal rat calvaria. PGE3 stimulated bone resorption with a potency similar to that of PGE2. However, EPA was a much less effective precursor for PGE3 than was arachidonic acid (AA) for PGE2. In bones cultured with complement sufficient rabbit serum, which stimulates endogenous PGE release, addition of EPA had little effect on bone resorption while AA produced a substantial increase. Bones labeled with [3H]-AA and incubated with transforming growth factor-alpha (TGF-alpha), which stimulates endogenous PGE production, produced substantial amounts of PGE2, while bones labeled with [3H]-EPA and treated similarly produced less than 1/10th as much labeled PGE3. Thus, EPA appears to be a less effective precursor for the production of bone resorbing prostanoids than AA in cultured rat bone. However, since PGE3 is a potent stimulator of bone resorption, the possibility that dietary EPA can effect the production of bone resorbing prostanoids in man requires further study