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Another antioxidant slows the advance of osteoporosis
Another antioxidant slows the advance of osteoporosis
Free Radic Biol Med. 2006 May 1;40(9):1483-93. Epub 2005 Dec 9.
Antioxidant alpha-lipoic acid inhibits osteoclast
differentiation by reducing nuclear factor-kappaB DNA
binding and prevents in vivo bone resorption induced by
receptor activator of nuclear factor-kappaB ligand
and tumor necrosis factor-alpha.
Kim HJ, Chang EJ, Kim HM, Lee SB, Kim HD, Su Kim G, Kim HH.
Department of Cell and Developmental Biology,
Brain Korea 21 Program, and Dental Research Institute,
Seoul National University School of Dentistry, 28
Yeongon-Dong, Chongno-Gu,
Seoul 110-749, Korea.
The relationship between oxidative stress and bone mineral density or
osteoporosis has recently been reported. As bone loss occurring in
osteoporosis
and inflammatory diseases is primarily due to increases in osteoclast
number,
reactive oxygen species (ROS) may be relevant to osteoclast
differentiation,
which requires receptor activator of nuclear factor-kappaB ligand
(RANKL). Tumor
necrosis factor-alpha (TNF-alpha) frequently present in inflammatory
conditions
has a profound synergy with RANKL in osteoclastogenesis. In this
study, we
investigated the effects of alpha-lipoic acid (alpha-LA), a strong
antioxidant
clinically used for some time, on osteoclast differentiation and bone
resorption.
At concentrations showing no growth inhibition, alpha-LA potently
suppressed
osteoclastogenesis from bone marrow-derived precursor cells driven
either by a
high-dose RANKL alone or by a low-dose RANKL
plus TNF-alpha (RANKL/TNF-alpha) alpha-LA abolished ROS elevation
by RANKL or RANKL/TNF-alpha and inhibited
NF-kappaB activation in osteoclast precursor cells. Specifically,
alpha-LA
reduced DNA binding of NF-kappaB but did not inhibit IKK activation.
Furthermore,
alpha-LA greatly suppressed in vivo bone loss induced by RANKL or TNF-
alpha in a
calvarial remodeling model. Therefore, our data provide evidence that
ROS plays
an important role in osteoclast differentiation through NF-kappaB
regulation and
the antioxidant alpha-lipoic acid has a therapeutic potential for bone
erosive
diseases.
PMID: 16632109
================================================
J Endocrinol. 2005 Jun;185(3):401-13.
Alpha-lipoic acid suppresses osteoclastogenesis despite
increasing the receptor activator of nuclear factor
kappaB ligand/osteoprotegerin ratio in human bone
marrow stromal cells.
Koh JM, Lee YS, Byun CH, Chang EJ, Kim H, Kim YH, Kim HH, Kim GS.
Division of Endocrinology and Metabolism,
Asan Medical Center,
University of Ulsan College of Medicine,
Seoul 138-736, Republic of Korea.
Growing evidence has shown a biochemical link between increased
oxidative stress
and reduced bone density. Although alpha-lipoic acid (alpha-LA) has
been shown to
act as a thiol antioxidant, its effect on bone cells has not been
determined.
Using proteomic analysis, we identified six differentially expressed
proteins in
the conditioned media of alpha-LA-treated human bone marrow stromal
cell line
(HS-5). One of these proteins, receptor activator of nuclear factor
kappaB ligand
(RANKL), was significantly up-regulated, as confirmed by
immunoblotting with
anti-RANKL antibody. ELISA showed that alpha-LA stimulated RANKL
production in
cellular extracts (membranous RANKL) about 5-fold and in conditioned
medium
(soluble RANKL) about 23-fold, but had no effect on osteoprotegerin
(OPG)
secretion. Despite increasing the RANKL/OPG ratio, alpha-LA showed a
dose-dependent suppression of osteoclastogenesis, both in a coculture
system of
mouse bone marrow cells and osteoblasts and in a mouse bone marrow
cell culture
system, and reduced bone resorption in a dose-dependent manner. In
addition,
alpha-LA-induced soluble RANKL was not inhibited by matrix
metalloprotease
inhibitors, indicating that soluble RANKL is produced by alpha-LA
without any
posttranslational processing. In contrast, alpha-LA had no significant
effect on
the proliferation and differentiation of HS-5 cells. These results
suggest that
alpha-LA suppresses osteoclastogenesis by directly inhibiting RANKL-
RANK mediated signals, not by mediating cellular RANKL production. In
addition, our findings indicate that alpha-LA-induced soluble RANKL is
not produced by shedding of membranous RANKL.
PMID: 15930166
===========================================
Free Radic Biol Med. 2006 May 1;40(9):1483-93. Epub 2005 Dec 9.
Antioxidant alpha-lipoic acid inhibits osteoclast
differentiation by reducing nuclear factor-kappaB DNA
binding and prevents in vivo bone resorption induced by
receptor activator of nuclear factor-kappaB ligand
and tumor necrosis factor-alpha.
Kim HJ, Chang EJ, Kim HM, Lee SB, Kim HD, Su Kim G, Kim HH.
Department of Cell and Developmental Biology,
Brain Korea 21 Program, and Dental Research Institute,
Seoul National University School of Dentistry, 28
Yeongon-Dong, Chongno-Gu,
Seoul 110-749, Korea.
The relationship between oxidative stress and bone mineral density or
osteoporosis has recently been reported. As bone loss occurring in
osteoporosis
and inflammatory diseases is primarily due to increases in osteoclast
number,
reactive oxygen species (ROS) may be relevant to osteoclast
differentiation,
which requires receptor activator of nuclear factor-kappaB ligand
(RANKL). Tumor
necrosis factor-alpha (TNF-alpha) frequently present in inflammatory
conditions
has a profound synergy with RANKL in osteoclastogenesis. In this
study, we
investigated the effects of alpha-lipoic acid (alpha-LA), a strong
antioxidant
clinically used for some time, on osteoclast differentiation and bone
resorption.
At concentrations showing no growth inhibition, alpha-LA potently
suppressed
osteoclastogenesis from bone marrow-derived precursor cells driven
either by a
high-dose RANKL alone or by a low-dose RANKL
plus TNF-alpha (RANKL/TNF-alpha) alpha-LA abolished ROS elevation
by RANKL or RANKL/TNF-alpha and inhibited
NF-kappaB activation in osteoclast precursor cells. Specifically,
alpha-LA
reduced DNA binding of NF-kappaB but did not inhibit IKK activation.
Furthermore,
alpha-LA greatly suppressed in vivo bone loss induced by RANKL or TNF-
alpha in a
calvarial remodeling model. Therefore, our data provide evidence that
ROS plays
an important role in osteoclast differentiation through NF-kappaB
regulation and
the antioxidant alpha-lipoic acid has a therapeutic potential for bone
erosive
diseases.
PMID: 16632109
================================================
J Endocrinol. 2005 Jun;185(3):401-13.
Alpha-lipoic acid suppresses osteoclastogenesis despite
increasing the receptor activator of nuclear factor
kappaB ligand/osteoprotegerin ratio in human bone
marrow stromal cells.
Koh JM, Lee YS, Byun CH, Chang EJ, Kim H, Kim YH, Kim HH, Kim GS.
Division of Endocrinology and Metabolism,
Asan Medical Center,
University of Ulsan College of Medicine,
Seoul 138-736, Republic of Korea.
Growing evidence has shown a biochemical link between increased
oxidative stress
and reduced bone density. Although alpha-lipoic acid (alpha-LA) has
been shown to
act as a thiol antioxidant, its effect on bone cells has not been
determined.
Using proteomic analysis, we identified six differentially expressed
proteins in
the conditioned media of alpha-LA-treated human bone marrow stromal
cell line
(HS-5). One of these proteins, receptor activator of nuclear factor
kappaB ligand
(RANKL), was significantly up-regulated, as confirmed by
immunoblotting with
anti-RANKL antibody. ELISA showed that alpha-LA stimulated RANKL
production in
cellular extracts (membranous RANKL) about 5-fold and in conditioned
medium
(soluble RANKL) about 23-fold, but had no effect on osteoprotegerin
(OPG)
secretion. Despite increasing the RANKL/OPG ratio, alpha-LA showed a
dose-dependent suppression of osteoclastogenesis, both in a coculture
system of
mouse bone marrow cells and osteoblasts and in a mouse bone marrow
cell culture
system, and reduced bone resorption in a dose-dependent manner. In
addition,
alpha-LA-induced soluble RANKL was not inhibited by matrix
metalloprotease
inhibitors, indicating that soluble RANKL is produced by alpha-LA
without any
posttranslational processing. In contrast, alpha-LA had no significant
effect on
the proliferation and differentiation of HS-5 cells. These results
suggest that
alpha-LA suppresses osteoclastogenesis by directly inhibiting RANKL-
RANK mediated signals, not by mediating cellular RANKL production. In
addition, our findings indicate that alpha-LA-induced soluble RANKL is
not produced by shedding of membranous RANKL.
PMID: 15930166
===========================================
