Alpha-lipoic acid and bone health -
Adherent cells were used as bone marrow macrophage BMM after washing out the nonadherent cells. For osteoclast formation assays, primary osteoblasts 2.
Cells positively stained for tartrate-resistant acid phosphatase TRAP and containing more than three nuclei were counted as osteoclasts. Some cultures were also treated with LA, DHLA, NAC, or GSH.
The concentration of PGE 2 in the culture medium was measured using an enzyme immunoassay EIA; Amersham Biosciences.
Western blotting analyses were performed as previously described The primary Abs used in this study were anti-cytosolic phospholipase A2 New England Biolabs , anti-cyclooxygenase-2 New England Biolabs , and anti-membrane-bound PGE synthase-1 mPGES-1 Cayman Chemical.
Blots were finally developed by using HRP-conjugated secondary Abs and visualized using ECL Amersham Biosciences. Total RNA was extracted from primary osteoblasts with TRIzol reagent, and cDNA was synthesized from 2 μg of total RNA by reverse transcriptase SuperScript II Preamplification System; Invitrogen Life Technologies.
Semiquantitative RT-PCR was performed on serial dilutions of each cDNA. PCRs were conducted for 21 cycles for mouse GAPDH or 26 cycles for mouse RANKL and OPG of 94°C for 30 s, 52°C for 30 s, and 72°C for 1 min.
The amplified cDNA fragments were run on 1. To study the effects of LA on ILinduced osteoclast formation in vivo, mice were implanted over the calvarial bones with collagen sponge treated with vehicle or IL-1 1 μg , then received injections i.
Bone loss induced by LPS administration was performed using previously described methods 12 with a slight modification.
Mice received injections i. The femurs were collected on day 8 after the first injection. The left femur of each animal was scanned with a high resolution microCT Skyscan microCT system; SkyScan.
The microCT system used an x-ray charge-coupled device camera with a cooled × pixel, bit sensor. Histological sections were prepared and stained for TRAP. All animal experiments were reviewed and approved by the Seoul National University School of Dentistry animal care committee.
All quantitative data are presented as the mean ± SD. Each experiment was performed four or five times, and results from one representative experiment are shown. We first examined the effect of LA on ILinduced osteoclast formation in cocultures of primary osteoblasts and bone marrow cells. Treatment with IL-1 for 7 days stimulated TRAP-positive osteoclast formation in the cocultures.
LA significantly inhibited osteoclast formation induced by IL-1 in a dose-dependent manner Fig. Almost complete inhibition, even in TRAP-positive mononucleated cells, was observed at 20 μM LA Fig.
To determine at which stage LA inhibits osteoclast formation, the cocultures were incubated with LA for 0—7, 0—3, or 3—7 days Fig. The incubation of LA during the early 0—3 days or late 3—7 days period significantly inhibited osteoclast formation compared with the control.
Thus, LA affected a molecule required for osteoclastogenesis in both periods. The inhibitory effect of LA was not due to cytotoxicity or reduced cell growth. Incubation of cocultures or BMM cultures with LA 10—50 μM for 48 h did not affect cell proliferation evaluated using the MTT assay data not shown.
To further characterize the effect of LA on osteoclast formation, osteoclasts were differentiated from BMM cultures in the presence of M-CSF and RANKL. The addition of LA had a minimal effect only at high concentrations on osteoclast formation from BMM cultures, unlike the potent effect observed in cocultures Fig.
LA inhibits osteoclast formation in cocultures treated with IL The cells were fixed and stained for TRAP.
TRAP-positive multinucleated cells containing three or more nuclei were counted as osteoclasts. B , LA 20 μM was added to the cocultures for the indicated days, and TRAP-positive multinucleated cells were counted as osteoclasts.
TRAP-positive multinucleated cells were counted. D , TRAP staining of cocultures in the presence of IL-1 upper panel , and BMMs in the presence of M-CSF and RANKL lower panel with or without LA 20 μM. IL-1 has been shown to promote osteoclastogenesis from osteoclast progenitors by regulating the expression of RANKL and OPG in osteoblasts or stromal cells Thus, we next analyzed the effects of LA on the expression levels of RANKL and OPG mRNA in osteoblasts by RT-PCR analysis.
Treatment of osteoblasts with IL-1 increased the expression level of RANKL mRNA within 1 h, and this effect was sustained for 72 h Fig. LA dose-dependently inhibited ILinduced RANKL expression at 72 h. However, LA did not affect the initial increase in RANKL expression by IL-1 Fig.
IL-1 reduced the OPG mRNA level at 72 h, and the presence of LA slightly attenuated this effect of IL These results indicate that the inhibitory effect of LA on ILinduced osteoclastogenesis was mainly due to suppression of RANKL expression in osteoblasts.
Therefore, we next examined whether the effect of LA could be overcome by supplying RANKL. The exogenous addition of RANKL significantly increased ILinduced osteoclast formation and recovered the inhibitory effect of LA on ILinduced osteoclast formation in cocultures Fig.
LA blocks the expression of RANKL mRNA induced by IL-1 in osteoblasts. Total RNA from the cells was isolated, and the expression levels of RANKL 26 cycles , OPG 26 cycles , and GAPDH 21 cycles mRNA were analyzed by RT-PCR.
TRAP-positive multinucleated cells were counted as osteoclasts. In our preliminary results, treatment with Vit D 10 nM or Vit D and PGE 2 nM induced osteoclast formation in cocultures, and LA 20 μM inhibited Vit D-induced, but not Vit D- and PGE 2 -induced, osteoclast formation data not shown.
PGE 2 in bone is produced mainly by osteoblasts and acts as a mediator of osteoclast formation in response to several cytokines, including IL-1 12 , 28 , In addition, PGE 2 increases RANKL expression in osteoblasts and stromal cells Thus, we examined whether LA affected PGE 2 synthesis induced by IL We measured the PGE 2 concentration in the culture medium of osteoblasts incubated with IL-1 in the presence or the absence of LA.
The addition of IL-1 to osteoblasts markedly induced PGE 2 production, and treatment with LA inhibited both basal and ILinduced PGE 2 production in a dose-dependent manner Fig. The addition of PGE 2 nM to the cocultures completely recovered ILinduced osteoclast formation in the presence of LA Fig.
These results imply that LA inhibited ILinduced PGE 2 production in osteoblasts and thereby prevented osteoclast formation in the cocultures. The inhibition of IL-1 induction of RANKL mRNA by LA was blocked by addition of PGE 2 Fig.
PGE 2 nM alone slightly increased RANKL expression, and this effect was not affected by treatment with LA Fig.
PGE 2 rescues ILinduced osteoclast formation suppressed by LA in cocultures. The PGE 2 concentration in the culture medium was determined by EIA. C , TRAP-positive multinucleated cells were counted as osteoclasts.
D , Primary osteoblasts were cultured in the presence or the absence of IL-1 with or without LA 20 μM or PGE 2 nM for 72 h. The expression levels of RANKL 26 cycles , OPG 26 cycles , and GAPDH 21 cycles mRNA were analyzed by RT-PCR. The inhibition of ILinduced osteoclast formation by LA was reversed by addition of either RANKL Fig.
In addition, PGE 2 restored ILinduced RANKL expression inhibited by LA in osteoblasts Fig. These results suggest that PGE 2 production induced by IL-1 is involved in RANKL expression in osteoblasts. To clarify the relationship between PGE 2 and RANKL expression, we used NS 1 μM , a specific inhibitor of COX Similar to the results with LA, NS inhibited ILinduced RANKL expression at 72 h, but not at 1 or 3 h Fig.
Treatment with NS slightly inhibited the down-regulation of OPG expression by IL-1 at 72 h. In line with the inhibitory effect on RANKL induction, NS blocked osteoclast generation from ILtreated cocultures Fig.
Furthermore, the addition of RANKL or PGE 2 rescued ILinduced osteoclast formation blocked by NS in the cocultures Fig. PGE 2 production is required to sustain RANKL expression in response to IL We next examined the effects of DHLA, the reduced form of LA, on ILinduced osteoclast formation.
IL-1 significantly induced the production of PGE 2 and RANKL mRNA Fig. Like LA, DHLA dose-dependently inhibited not only the production of PGE 2 Fig. The addition of PGE 2 rescued ILinduced expression of RANKL in LA-treated osteoblasts Fig.
DHLA also abolished ILinduced osteoclast formation in the cocultures, which was reversed by the addition of PGE 2 Fig. Furthermore, DHLA, except at the highest concentration, had no significant effect on osteoclast formation from BMMs treated with M-CSF and RANKL Fig. DHLA inhibits ILinduced osteoclast formation from cocultures.
C , The cocultures were cultured in the presence of IL-1 with or without DHLA 20 μM or PGE 2 nM for 7 days. We then examined how LA inhibited ILinduced PGE 2 production.
LA inhibited ILinduced PGE 2 production in osteoblasts even in the presence of arachidonic acid 5 μM; Fig. This result implies that LA inhibits the step required for the conversion of arachidonic acid to PGE 2.
Previous reports have indicated that the production of PGE 2 in response to IL-1 and LPS is dependent on the elevation of COX-2 and mPGES-1 expression 12 , In our study, treatment of osteoblasts with IL-1 for 24 h stimulated the protein expression of cytosolic phospholipase A 2 cPLA 2 , COX-2, and mPGES-1 Fig.
LA did not affect basal and ILinduced protein levels Fig. We then checked COX-2 activity in vitro. DHLA and GSH, but not LA, decreased the peroxidase activity of human rCOX-2 Fig. GSH and NAC had a weak effect only at high concentrations on ILinduced PGE 2 production in osteoblasts Fig.
Taken together, these results suggest that LA enters the cells, is reduced to DHLA, and suppresses ILinduced PGE 2 production by, at least in part, inhibiting COX-2 activity.
LA inhibits PGE 2 production by inhibiting COX-2 activity. Whole-cell lysates were subjected to Western blotting with the indicated Abs. C , Human rCOX-2 was incubated with LA 10 and 20 μM , DHLA 10 and 20 μM , or GSH 20 and μM , and the COX-2 activity assay was conducted as indicated in Materials and Methods.
The PGE 2 concentration in the culture medium was determined. To examine the effects of LA on ILinduced osteoclast formation in vivo, we implanted a collagen sponge treated with or without IL-1 over the calvarial bones of mice.
IL-1 significantly increased the number of osteoclasts and the resorbed area in calvarial bone, and this effect was inhibited by daily injection of LA Fig.
The same parameters were not appreciably changed in the presence of LA alone. LA inhibits bone loss by IL-1 and LPS in vivo. A , Mice implanted over the calvarial bones with a collagen sponge treated with or without IL-1 1 μg received injections i.
Calvarias were stained for TRAP. To examine the effect of LA on LPS-induced bone loss, mice received injections i. B , Bone phenotype at the distal metaphysis of femur was analyzed by microCT. C , Decalcified sections of the femurs were stained for TRAP to detect osteoclasts. LPS, a major constituent of Gram-negative bacteria, has been reported to induce osteoclast formation in bone marrow cultures, and the administration of LPS stimulates osteoclastic bone resorption in part through elevation of PGE 2 production in vivo 12 , To determine the influence of LA on bone loss induced by LPS administration, mice received injections with LPS with or without LA.
The microCT analysis showed that LPS injection caused a marked bone loss, especially in the distal metaphysis of the femur. The loss of cancellous bone induced by LPS was significantly inhibited by daily injection of LA Fig.
To determine the inhibitory effect of LA on LPS-induced bone loss, histological sections of distal femoral metaphysis were prepared and stained for TRAP.
The injection of LPS significantly increased the number of osteoclasts in trabecular bone. In contrast, the number of osteoclasts in trabecular bone treated with LPS and LA was similar to that in the control Fig. These results imply that the inhibitory effect of LA on IL or LPS-induced bone loss is due to the reduced number of osteoclasts.
Production of IL-1 is involved in osteoporosis induced by both estrogen deficiency and inflammation. Mice lacking the type I IL-1R are resistant to bone loss after ovariectomy Blocking the effects of IL-1 with IL-1R antagonists, anti-IL-1 mAbs, or soluble IL-1 type II receptors significantly reduces bone erosions and cartilage degradation in animal models of rheumatoid arthritis In this study the addition of LA prevented osteoclast differentiation from cocultures by IL-1, but not from BMMs treated with M-CSF and RANKL Fig.
LA significantly inhibited sustained RANKL expression in osteoblasts, without affecting its initial elevation by IL-1, and the exogenous addition of RANKL to the cocultures rescued the inhibitory effects of LA on osteoclast formation Fig.
These results suggest that LA inhibited ILinduced osteoclast formation in the cocultures by inhibiting RANKL expression in osteoblasts, and that a factor required for maintenance of the up-regulated RANKL expression level might have been induced by IL Previous reports have shown that several proresorptive factors, including IL-1 12 , 28 , TNF-α 28 , LPS 29 , and parathyroid hormone 33 , stimulate osteoclast formation through PGE 2 -dependent mechanisms.
We found that LA completely inhibited PGE 2 production by IL-1 in osteoblasts, and the exogenous addition of PGE 2 rescued not only RANKL expression in osteoblasts, but also osteoclast formation in cocultures, both suppressed by LA Fig.
Using NS, we also found that PGE 2 production was required for the maintenance of RANKL expression by IL-1 Fig. These results indicate that LA decreases RANKL expression by inhibiting PGE 2 synthesis in osteoblasts, thereby preventing osteoclast formation in the cocultures treated with IL PGE 2 synthesis is regulated by three metabolic steps: the release of arachidonic acid from phospholipids, the conversion to PGH 2 , and the synthesis of PGE 2 by PLA 2 , COX, and PGES It was recently reported that cPLA2 is expressed in mouse osteoblasts and is the key enzyme in PGE 2 synthesis in response to IL-1 and LPS The two COX enzymes are encoded by separate genes and differentially expressed.
Although constitutive COX COX-1 and inducible COX COX-2 are both expressed in mouse osteoblasts, COX-2 is largely responsible for PGE 2 synthesis in osteoblasts after stimulation by several agonists 29 , At least three distinct PGES isoforms have been identified: cytosolic PGES cPGES , mPGES-1, and mPGES Cytosolic PGES is constitutively and ubiquitously expressed and is preferentially coupled with COX In contrast, mPGES-1 is up-regulated by proinflammatory stimuli and is functionally coupled with COX-2; mPGES-2 is ubiquitously expressed in diverse tissues, but the role of mPGES-2 remains to be elucidated 34 , Four PGE 2 receptor subtypes have been cloned in mice and thoroughly characterized.
The EP4 subtype of the PGE 2 receptor on osteoblasts is involved in osteoclast formation by LPS, TNF-α, and IL-1 Therefore, PGE 2 production caused by increased expression or activity of cPLA2, COX-2, and mPGES-1 in osteoblasts after treatment with LPS or proinflammatory cytokines might increase osteoclast formation through the EP-4 subtype on osteoblasts.
LPS and proinflammatory cytokines, including IL-1, promote PGE 2 production by increasing COX-2 expression in a manner dependent on NF-κB activation 36 , NF-κB has been proposed to be a redox-sensitive transcription factor 38 , and LA inhibited TNF-α-induced NF-κB by inhibiting the activities of IκB kinase However, in this study LA 20 μM inhibited PGE 2 synthesis by IL-1 even in the presence of arachidonic acid, without affecting the protein expression level of cPLA2, COX-2, and mPGES in osteoblasts Fig.
Thus, it is unlikely that LA 20 μM affects ILinduced signaling pathways, including NF-κB activation, required for the increases in the enzymes involved in PGE 2 biosynthesis. COX, a heme-containing protein, is a bifunctional enzyme exhibiting both COX and peroxidase activities.
The COX component converts arachidonic acid to PGG 2 , and the peroxidase component reduces the endoperoxide to PGH 2 Endogenous radicals are required to activate newly made COX holoenzymes by forming tyrosyl radical at Tyr , which is crucial for the catalytic activity.
Lipid peroxides and peroxynitrite have both been implicated as the oxidants that oxidize ferric heme to a ferryl-oxo protoporphyrin radical Previous reports have shown that LA can regenerate endogenous and exogenous antioxidants and scavenge free radicals, including lipid peroxides and peroxynitrite, in cells 13 , 41 , Thus, this antioxidant property of LA may be involved in the inhibition of COX-2 and the subsequent decrease in PGE 2 synthesis.
It was also recently reported that DHLA, but not LA or the hydrophilic thiol NAC, inhibits lipid peroxidation by lipoxygenase, a member of the family of nonheme iron-containing dioxygenases This effect was suggested to stem primarily from the reduction of the active ferric lipoxygenase form to the inactive ferrous state after hydrophobic interaction between DHLA and the enzyme and, possibly, from scavenging of fatty acid peroxyl radicals formed during lipoperoxidative processes In our study DHLA, but not LA, decreased the peroxidase activity of human rCOX-2 Fig.
Given that DHLA, but not GSH, is hydrophobic 17 and that mPGES and both COX isoenzymes are localized in the perinuclear envelope 44 , DHLA may be more effective to inhibit COX-2 activity and PGE 2 production than GSH in cells. However, hydrophobicity may not be a factor that affects the activities of those thiol oxidants in an in vitro assay system of COX In addition, GSH can function as a cofactor of PGES in vivo 45 , 46 , which compensates for the inhibition of COX-2 by GSH.
We also found that the i. administration of LA could reduce osteoclast formation and bone loss induced by IL-1 in parietal bone Fig. Recently, it was reported that i.
Thus, these results suggest that exogenous application of LA reduces bone destruction in inflammatory conditions.
In this study, we showed that LA inhibited PGE 2 synthesis by inhibiting COX-2 activity. Our results indicate the possibility that LA could have beneficial effects on preventing several diseases mediated by PGE 2 overproduction as well as osteoclastic bone loss associated with inflammation.
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Section solely to indicate this fact. Abbreviations used in this paper: RANKL, receptor activator of NF-κB ligand; BMM, bone marrow macrophage; COX-2, cyclooxygenase-2; cPLA 2 , cytosolic phospholipase A 2 ; DHLA, dihydrolipoic acid; EIA, enzyme immunoassay; GSH, glutathione; LA, α-lipoic acid; NAC, N -acetyl- l -cysteine; OPG, osteoprotegerin; TRAP, tartrate-resistant acid phosphatase; Vit D, 1,dihydroxyvitamin D 3 ; PGE 2 , prostaglandin E 2 ; mPGES-1, membrane-bound PGE synthase Sign In or Create an Account.
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Skip Nav Destination Close navigation menu Article navigation. Volume , Issue 1. Materials and Methods. Cell cultures. In vitro osteoclast cultures. Measurement of PGE 2 content. Western blot analysis. In vitro recombinant cyclooxygenase-2 COX-2 activity.
Semiquantitative RT-PCR analysis. In vivo experiments. Statistical analysis. LA inhibits osteoclast formation by IL-1 in cocultures. LA interferes with the sustained expression of RANKL induced by IL PGE 2 rescues ILinduced osteoclast formation inhibited by LA.
PGE 2 is required for sustained expression of RANKL by IL DHLA prevents ILinduced osteoclast formation. LA decreases PGE 2 production by inhibiting COX-2 activity.
LA prevents inflammation-induced bone destruction. Article Navigation. Research Article January 01 α-Lipoic Acid Inhibits Inflammatory Bone Resorption by Suppressing Prostaglandin E 2 Synthesis 1 Hyunil Ha ; Hyunil Ha.
Department of Cell and Developmental Biology, DRI, BK21 Program, Seoul National University College of Dentistry, Seoul, Korea. This Site. Google Scholar. Jong-Ho Lee ; Jong-Ho Lee. Ha-Neui Kim ; Ha-Neui Kim. Hyun-Man Kim ; Hyun-Man Kim. Han Bok Kwak ; Han Bok Kwak. Seungbok Lee ; Seungbok Lee.
Hong-Hee Kim ; Hong-Hee Kim. Zang Hee Lee Zang Hee Lee. Received: June 07 Accepted: October 20 Published: January 01 Online ISSN: Copyright © by The American Association of Immunologists. J Immunol 1 : — Article history Received:.
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FIGURE 2. FIGURE 3. FIGURE 4. FIGURE 5. FIGURE 6. Dietary protein is essential for bone mass, not only does it increase during childhood and adolescence, but also preserves bone mass with ageing. Lack of protein strips the muscles of strength, which increases the risk of falls, and contributes to poor recovery in patients who have had a fracture.
Animal sources of protein include lean red meat, poultry and fish, as well as eggs and dairy foods. Vegetable sources of protein include legumes e.
lentils, kidney beans , soy products e. tofu , grains, nuts and seeds. It is recommended to have good fats in the diet, as they increase pro-inflammatory cytokines and decrease systemic inflammation Halade et al.
Good fats include avocados, ghee, coconut oil, fatty fish sardines, mackerel and sardines , eggs and some nuts and seeds. Magnesium is vital for the production and formation of bone mineral.
The elderly are often at risk of mild magnesium deficiency, as the absorption of magnesium decreases with age. Green vegetables, legumes, nuts, seeds, unrefined grains and fish are good sources of magnesium.
Another mineral that is important for bone tissue renewal and mineralisation is Zinc; deficiencies are associated with calorie and protein malnutrition, and contribute to impaired bone growth in children. Zinc deficiency has also been reported in the elderly and can contribute to poor bone status.
Sources of zinc include lean red meat, poultry, whole grain cereals, pulses, legumes and pumpkin seeds best when soaked overnight. Supplementing with alpha lipoic acid ALA can aid in improving bone health; its bioactive compound can dispose of heavy metals and regenerate vitamins C and E.
Also, ALA has antioxidant properties and can reduce oxidative stress as well as inflammation; oxidative stress and systemic inflammation accelerate bone loss causing osteoporosis. ALA reduces bone loss by lowering oxidative stress and inflammation, which slows osteoclastic bone-resorbing activity.
Another supplement that is known to improve symptoms of osteoporosis is berberine; research suggests that berberine may lower osteoclast activity and boost osteoblast activity. This article was written by Isha Patel, an expert Nutritionist at Perfect Balance Clinic. They can help you take control of your osteoporosis by making adjustments to your nutrition, lifestyle and exercise routine to help you be pain free, and get you feeling fit and healthy.
If you are a healthcare professional, we offer a range of healthcare CPD courses, including this osteoporosis webinar. Let us introduce you to an Osteoporosis Specialist with our free service, Oryon Connect.
You can get an appointment with a specialist like Isha quickly, efficiently and at an affordable price, to help you to live comfortably.
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Iseme, R. and Attia, J. Is osteoporosis an autoimmune mediated disorder?. Bone Reports, 7, pp. Diet Online, Chen, S. and Kao, C. Osteoporosis Is Associated With High Risk for Coronary Heart Disease.
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Jump to main content. Contact Us. Citation Tags HERO ID. Reference Type. Journal Article.Alpha-lipoic acid and bone health -
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These factors are driving current interest in the clinical use of naturally occurring bioactive compounds to mitigate bone loss. Alpha-lipoic acid, a potent antioxidant and essential member of mitochondrial dehydrogenases, has shown considerable promise as an antiosteoclastogenic agent due to its potent reactive oxygen species-scavenging capabilities along with a proven clinical safety record.
Collectively, current data indicate that alpha-lipoic acid protects from bone loss via a 2-pronged mechanism involving inhibition of osteoclastogenic reactive oxygen species generation and upregulation of redox gene expression. Keywords: NF-κB; RANKL; alpha-lipoic acid; bone loss; osteoblast; osteoclast; osteoporosis; oxidative stress.
Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved.
Joseph L. Alph-alipoic Alpha-lipoic acid and bone health a chronic disease associated Electrolyte Absorption decreased bone density that afflicts millions of people Digestive health support. Current pharmacological treatments are bons, costly, and linked to Alpha-lipooic negative side effects. These factors are driving current interest in the clinical use of naturally occurring bioactive compounds to mitigate bone loss. Alpha-lipoic acid, a potent antioxidant and essential member of mitochondrial dehydrogenases, has shown considerable promise as an antiosteoclastogenic agent due to its potent reactive oxygen species-scavenging capabilities along with a proven clinical safety record.
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