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•
Note: The following is a limited selection of abstracts from 1994
to present.
•
Due to length, we present this as a separate section
• Click here to return to the 4-part Bone
section for fluorine & organofluorine pesticides.
•
When time allows more information will be added.
•
Fluoride
& Bone Damage: Published Data.
Compiled by Michael Connett (also see Letter
for this submission)
January
29, 2004. Submission
to the National Research Council
"Subcommittee on the Toxicologic Risk of Fluoride in
Drinking Water; BEST-K-02-05-A".
See
TABLE 1: Bone
& Teeth Effects Associated with Water Fluoride Content
TABLE 2: Bone
Effects Associated with Daily Doses of Fluoride
TABLE 3a: Average
Serum Fluoride Levels Reported in Human Skeletal Fluorosis
TABLE 3b: Serum
Fluoride Levels Causing Damage to Mineralized Tissues
in Rats
TABLE 4a: Bone
Effects Associated with Bone Fluoride Content (BFC)
TABLE 4b:
Maximum Fluoride Bone Concentrations in Humans Living
in < 1.9 ppm areas
Table 5a:
Bone Effects Associated with Urine Fluoride Content
Table 6:
Variations in Individual Susceptibility to Skeletal Fluorosis:
Duration of Exposure which Produces the Disease
•
Comments
submitted in response to the invited presentations of Dr.
Gary Whitford and Dr. Charles Turner on fluoride and bone
to the National Research Council "Subcommittee on the
Toxicologic Risk of Fluoride in Drinking Water; BEST-K-02-05-A".
November 10, 2003. Submitted
by Michael Connett
•
A safe
drinking water standard for fluoride: LOAELs and protecting
the most vulnerable
- (a major part of this paper focuses on fluoride and bone)
August 12, 2003. Presentation
to the
National Research Council "Subcommittee on the Toxicologic
Risk of Fluoride in Drinking Water; BEST-K-02-05-A".
Paper prepared by:
Paul Connett, PhD
Professor of Chemistry, St. Lawrence University, Canton,
NY 13617
&
Michael Connett
Research Assistant, Fluoride Action Network
|
A
New Jersey Department of Health study found that
the rate of osteosarcoma occurred at higher rates in young males
from fluoridated versus unfluoridated areas. Between the years 1970
and 1989, the rate of osteosarcoma
(among 10-19 year old males) was found to be 3.5 to 6.3 times greater
in the fluoridated versus unfluoridated areas.
Ref: Cohn PD. (1992). A Brief Report On The
Association Of Drinking Water Fluoridation And The Incidence of
Osteosarcoma Among Young Males. New Jersey Department of Health
Environ. Health Service: 1- 17.
Abstract: The
US National Toxicology Program has shown equivocal evidence of carcinogenic
activity of sodium fluoride (NaF) in male F344/N rats based on the
occurrence of five osteosarcomas in treated animals. In the study
the osteosarcomas developed mainly in the rat vertebrae. To provide
a possible mechanistic basis for the observed tumors, the genotoxic
effects of NaF on the possible target organ of NaF carcinogenesis
were examined. Rat vertebral body-derived (RVBd) cells were established
from trabecular bone of vertebral bodies of a male F344/N rat 6
weeks of age and treated with NaF. RVBd cells in secondary culture
exhibited a high level of alkaline phosphatase (ALP) activity when
the cells at confluence were assayed by ALP staining. When the histochemical
examination was performed on RVBd cell colonies, most of the colonies
were stained positively for ALP. Confluent RVBd cells were responsive
to 10(-8) M 1 alpha.25-dihydroxyvitamin D3 with a 7.7-fold increase
in osteocalcin production over base line values. The von Kossa staining
demonstrated that in the presence of 2 mM beta-glycerophosphate,
RVBd cells that were allowed to grow past confluence for approximately
2 months formed mineralized nodules. When RVBd cells in tertiary
culture were treated with NaF at 0.5-2.0 mM for 24-72 h, the growth
and/or survival of the treated cells was reduced in a dose-dependent
manner. Significant increases in the frequencies
of chromosome aberrations were induced in a dose- and treatment
time-dependent fashion when NaF was administered to RVBd cells at
0.5 and 1.0 mM for 24 and 48 h. The results indicate that NaF is
genotoxic to rat vertebrae, providing a possible mechanism for the
vertebrae, as a target organ of NaF carcinogenesis.
Ref: Mutat
Res. 1996 May;368(1):7-13. Clastogenic activity of sodium fluoride
to rat vertebral body-derived cells in culture.
Mihashi M, Tsutsui T.
In a 1990
National Toxicology Program fluoride rat study, a statistically-significant,
dose-dependent trend increase in osteosarcoma among the fluoride-treated,
male rats was reported. According to a review of NTP's findings
by the World Health Organization:
In male F344/N rats receiving 0.2, 0.8, 2.5 or 4.1 mg fluoride/kg
body weight per day, the incidence of osteosarcomas (three tumours
in the vertebra and one in the humerus) was 0/80, 0/51, 1/50 and
3/80, respectively (NTP, 1990). A pairwise comparison of the incidence
in the high-dose group versus controls was not statistically significant
(P = 0.099); if an extraskeletal osteosarcoma, located in the
subcutis of the flank of one high-dose male rat, was included
in the total tumour incidence in this group of animals, the pairwise
comparison with the control group remained statistically insignificant
(P = 0.057). However, the osteosarcomas
occurred with a statistically significant (P = 0.027, by logistic
regression) dose-response trend (NTP, 1990) ...In
assessing the evidence for the carcinogenicity of fluoride derived
from studies conducted with laboratory animals, some significance
might be attributed to the observation of a dose–response
trend in the occurrence of osteosarcomas in male F344/N rats administered
sodium fluoride in drinking-water (NTP, 1990). Such a trend
associated with the occurrence of a rare tumour in the tissue
in which fluoride is known to accumulate cannot be casually dismissed.
Ref:
FLUORIDES. Environmental Health Criteria 227. World Health Organization,
Geneva. 224 page report released August 8, 2002.
http://www.inchem.org/documents/ehc/ehc/ehc227.htm
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14650182&dopt=Abstract
Wei Sheng Yan Jiu 2003
. Sep;32(5):432-3.
[Effects of fluoride on cell cycle and apoptosis in cultured
osteoblasts of rats]
[Article in Chinese]
Zhang Y, Sun G, Jin Y, Wang Y.
School of Public Health, China Medical University, Shenyang 110001,
China.
To study the effects of fluoride on cell growth, cell cycle and
apoptosis in cultured osteoblasts of rats. The enzymes digesting
method was used to isolate the osteoblasts of rats. The activity
of the cells was determined by the percents of reduced AlamarBlue.
FCM was used to analyze cell cycle and apoptosis. The results showed
that the activity of rat osteoblast was not influenced by NaF at
0 to 2 mmol/L concentration after 24 hours incubation. At the concentration
of 2 mmol/L, the number of cells at S phase was increased. At the
concentration of 4 mmol/L, NaF increased the number of cells at
S phase and at the same time, decreased the number of cells at G2/M
phase, but the number of the cells at G0/G1 phase kept unchanged.
The percent of apoptosis was increased at the concentration of 2
mmol/L. Excessive fluoride could affect the
cell activity, retarded cell cycle at S phase and induced apoptosis.
PMID: 14650182 [PubMed - in process]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12930673&dopt=Abstract
Zhonghua Yu Fang Yi Xue
Za Zhi. 2003 Jul;37(4):246-50.
[Expression
of proto-oncogenes c-fos and c-jun in osteoblasts
activated by excessive fluoride]
[Article in Chinese]
Zhang
WL, Cui YN, Gao S, Zhang XY, Li GS.
Department of Pathology,
Institute of Endemic Disease, Jilin University, Changchun 130021,
China.
OBJECTIVE: To study expression
of proto-oncogenes c-fos and its accompanying gene c-jun in osteoblasts
activated by action of excessive fluoride in vivo and in vitro.
METHODS: Experimental Wistar rats were exposed to sodium
fluoride (NaF) added to their drinking water, and NaF was
also added in cell culture supernatant for osteoblast-like cells
in vitro. Expression of both mRNA and protein of c-fos and c-jun
in bone-tissue of rats with chronic fluorosis and cultured osteoblast-like
cells were determined by hybridization in situ, Western blot and
immunohistochemistry at varied time periods after exposure.
RESULTS: Sodium fluoride could stimulate the proliferation of osteoblast
in rats with chronic fluorosis and induce expression of both c-fos
and c-jun in all envelops of the spine bone, as compared with its
control group. Value of optical absorption in mRNA expression of
c-fos and c-jun was 139.63 and 126.37, respectively, in rats with
NaF plus high-calcium, significantly lower than that in control
group with high-calcium only (107.74 and 117.48, respectively) (P
< 0.001). Immunohistochemical analysis showed that protein level
of c-fos and c-jun was significantly higher in rats with NaF plus
high-calcium than that in control rats with high-calcium only, with
values of optical absorption of 139.16, 131.15, 149.98 and 149.19
(P < 0.05), respectively, and protein level of c-fos and c-jun was
signifcantly higher in rats with NaF plus low-calcium than that
in control rats with low-calcium only, with values of optical absorption
of 117.24, 111.46, 132.46 and 129.79 (P < 0.05), respectively. Western
blotting showed that level of protein expression of c-fos and c-jun
in periosteal osteoblasts was significantly higher in all rat groups
with NaF than that in all control groups, with values of optical
absorption of 123.32, 116.60, 115.97 and 108.30, respectively. mRNA
expression of c-fos and c-jun in osteoblast-like cells treated with
NaF for 12 h increased obviously, and remained at high level 48
h after exposure, with values of optical absorption of 114.80, 161.14,
118.20, and 150.41, respectively, as compared with that in control
group (P < 0.001 and P < 0.05).
CONCLUSIONS: Exposure to excessive fluoride
could stimulate activation and proliferation of both osteoblasts
in rats and cultured osteoblast-like cells in vitro, and cause enhanced
expression of mRNA and protein
of both c-fos and c-jun. Over-expression of c-fos could play an
important role in development and proliferation of skeletal lesions
in rats with chronic fluorosis.
PMID: 12930673
[PubMed - in process]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12930672&dopt=Abstract
Zhonghua Yu Fang Yi Xue
Za Zhi. 2003 Jul;37(4):243-5.
[Expression
of type II collagen gene and structural change
in bone tissues of rats with experimental fluorosis]
[Article in Chinese]
Liu BC, Xu ZL, Miao Q, Xu YY, Xu M, Qian
XJ, You BR, Yuan BH, Kang N.
National Institute of Occupational Health and Poison Control, Chinese
Center for Disease Control and Prevention, Beijing 100050, China.
OBJECTIVE: To investigate the effects of excessive intake of fluoride
on the expression of type II collagen gene and types and morphological
change of collagen fiber in the bone tissues of rats.
METHODS: A rat model with fluorosis was established by adding 221
mg/L of sodium fluoride (NaF) to drinking water for the rats for
15 days, 30 days and two months, respectively. Type II collagen
alpha1 (II) cDNA probe was prepared, and cDNA-mRNA in-situ hybridization
was employed to detect change in expression of type II collagen
mRNA in the bone tissues of rats with excessive intake of fluoride
(221 mg/L NaF). Picrosirus-polarization method was used to observe
types of collagen and morphology of collagen fiber in the bone tissues.
RESULTS: Chondroblasts were found in the femur and other bone tissues
of the rats after exposure to fluoride. cDNA-mRNA in-situ hybridization
showed that expression of type II collagen gene could be observed
in the cytoplasm of chondrocytic lacuna and chondrified bone tissues.
mRNA in collagen of chondrocytes of the rib cartilage reached the
peak level 15 days after exposure to fluoride, and decreased gradually
one month and two months after exposure. Polychromatic type II collagen,
breakage of collagen fiber, disorder array and reduced content of
type II collagen could be found in the bone tissues with picrosirius-polarization
method.
CONCLUSIONS: Excessive intake of fluoride
could lead to changes in types and structure of collagen (cross-linkage)
of bone tissues, which caused expression of type II collagen gene
in the chondrified bone tissues and enhanced its expression in the
rib cartilage tissues.
PMID: 12930672 [PubMed - in process]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11512573&dopt=Abstract
J Epidemiol 2001 Jul;11(4):170-9
Regression analysis of
cancer incidence rates and water fluoride
in the U.S.A. based on IACR/IARC (WHO) data (1978-1992).
International Agency for Research on Cancer.
Takahashi
K, Akiniwa K, Narita K.
Department of Physical Medicine, Faculty of Medicine, University
of Tokyo, Japan.
Age-specific and age-standardized rates (ASR) of registered cancers
for nine communities in the U.S.A. (21.8 million inhabitants, mainly
white) were obtained from IARC data (1978-82, 1983-87, 1988-92).
The percentage of people supplied with "optimally"
fluoridated drinking water (FD) obtained from the Fluoridation
Census 1985, U.S.A. were used for regression analysis of incidence
rates of cancers at thirty six sites (ICD-WHO, 1957). About two-thirds
of sites of the body (ICD) were associated positively with FD, but
negative associations were noted for lip cancer, melanoma of the
skin, and cancers of the prostate and thyroid gland. In digestive
organs the stomach showed only limited and small intestine no significant
link. However, cancers
of the oral cavity and pharynx, colon and rectum, hepato-biliary
and urinary organs were positively associated
with FD. This was also the case for
bone cancers in male, in line with results of rat experiments.
Brain tumors and T-cell system Hodgkin's disease,
Non-Hodgkin lymphoma, multiple myeloma, melanoma of the skin and
monocytic leukaemia were also correlated with FD. Of the
36 sites, 23 were positively significant (63.9%), 9 not significant
(25.0%) and 4 negatively significant (11.1%). This may indicate
a complexity of mechanisms of action of fluoride in the body, especially
in view of the coexising positive and negative correlations with
the fluoridation index. The likelihood of fluoride acting as a genetic
cause of cancer requires consideration.
PMID: 11512573 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11855746&dopt=Abstract
Mol Cell Biochem
2001 Dec;228(1-2):91-8
Differential
effects of bacterial toxins on mitogenic actions of sodium
fluoride and those of aluminum fluoride
in human TE85 osteosarcoma cells.
Hashimoto
H, Lau KH.
Department of Medicine, Loma Linda University, Jerry L. Pettis Memorial
VA Medical Center, CA 92357, USA.
This study compared
the effects of cholera toxin (CTX) and pertussis toxin (PTX) on
the actions of sodium fluoride (NaF)
and those of aluminum fluoride (AlF3)
on cell proliferation and differentiation, as well as tyrosine phosphorylation
level of mitogen activated protein kinase (MAPK) in human bone cells.
NaF and AlF3
each significantly stimulated the proliferation
of human TE85 osteosarcoma cells, increased cellular alkaline phosphatase
(ALP) activity, and increased MAPK tyrosine phosphorylation level.
CTX completely blocked the bone cell anabolic activities of both
NaF and AlF3.
While PTX (2 ng/ml) inhibited the bone cell actions of NaF,
it had no significant effect on those of AlF3.
Both CTX and PTX completely blocked the stimulatory action of AlF3
on MAPK tyrosine phosphorylation, but neither toxin had an effect
on the action of NaF on MAPK tyrosine
phosphorylation. In conclusion, PTX and CTX had contrasting effects
on the anabolic bone cell actions of NaF
and AlF3 actions. These findings argue
against the hypothesis that the osteogenic activity of NaF
is mediated via the formation of AlF3
in human TE85 osteosarcoma cells.
PMID: 11855746 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11797833&dopt=Abstract
J Environ Pathol Toxicol
Oncol 2001;20(3):237-43
Low levels
of p53 mutations in Indian patients with osteosarcoma
and the correlation with fluoride levels in bone.
Ramesh
N, Vuayaraghavan AS, Desai BS, Natarajan M, Murthy PB, Pillai KS.
Frederick Institute of Plant Protection and Toxicology, Padappai,
Tamil Nadu, India.
The pathogenesis of osteogenic sarcoma is not known. Recently, chronic
fluoride exposure has been incriminated
as having a possible etiologic role by causing a nonspecific osteoblast
proliferation. We were interested in exploring the possible relationship
between fluoride bone content and p53
mutations. We analyzed p53 mutations in various exons in tissue
of osteosarcoma, and correlated the findings with the bone
fluoride levels in Indian patients. We analyzed tissue samples
from 20 osteosarcoma patients for possible genetic alterations including
mutations, and
we assessed the extent of fluoride accumulation
in bone. Fragments displaying an altered
electrophoretic mobility were confirmed as having mutated sequences.
Mutation was observed in samples of two cases (10% incidence).
Eighteen samples showed bone fluoride
levels between 1000 and 27,000 ppm, whereas the 2 mutated samples
showed fluoride levels of 64,000 and
89,000 ppm, respectively. The high
levels of bone fluoride levels and the similarity of the mechanisms
of action between fluoride-induced DNA damage and chemically-induced
p53 mutations lead us to propose that high fluoride bone content
might have been one of the major factors causing osteosarcoma.
PMID: 11797833 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11434994&dopt=Abstract
Food Chem Toxicol 2001
Aug;39(8):867-76
Developmental
toxicity of sodium fluoride measured
during multiple generations.
Collins
TF, Sprando RL, Black TN, Shackelford ME, Olejnik N, Ames MJ, Rorie
JI, Ruggles DI.
Center for Food Safety and Applied Nutrition, US
Food and Drug Administration, 8301 Muirkirk Road, Laurel,
MD 20708, USA. tcoll60504@aol.com
Sodium fluoride (NaF) has been used to fluoridate drinking water
in the United States since the mid 1940s. Because of the lack of
reliable studies on the multigeneration effects of the compound,
NaF (0, 25, 100, 175 or 250 ppm in drinking water) was given to
rats continuously during three generations. Parental (F0) generation
rats were treated for 10 weeks and mated within groups. At gestation
day 20, caesarean sections were performed and eight F0 females per
group and their litters (F1) were observed for implant status, fetal
weight and length, sex and morphological development. The remaining
F0 females (29-32 per group) were allowed to litter. F1 offspring
(36 of each sex per group) were mated within groups, and caesarean
sections were performed at gestation day 20. The F1 females and
their litters (F2) were observed for implant status, fetal weight
and length, sex and morphological development. In addition, F2 fetuses
were evaluated for internal (soft-tissue) and skeletal development.
Decreased fluid consumption for F0 and F1 dams at 175 and 250 ppm
was attributed to decreased palatability of the solution. No dose-related
effects in feed consumption or mean body weight gain were observed
in either F0 or F1 females. Numbers of corpora lutea, implants,
viable fetuses and fetal morphological development were similar
in all groups. No dose-related anomalies in internal organs were
observed in F2 fetuses. Ossification of the
hyoid bone of F2 fetuses was significantly decreased at 250 ppm.
Because of the decreased ossification of the hyoid bone, 250 ppm
is considered the effect level.
PMID: 11434994 [PubMed - indexed for MEDLINE]
•
Note from EC:
-- Sprando and Collins are unique
among scientists who research fluoride as they do not find adverse
effects at low dose levels. While Sprando and Collins findings
conflict with the majority of researchers who have published on
numerous experiments, they are in agreement with, and cited by,
US regulatory agencies.
-- Definition of Hyoid bone: a U-shaped
bone lying between the mandible and the larynx, suspended from
the styloid processes by slender stylohyoid ligaments. Ref: Steadman's
Concise Medical Dictionary for the Health Professions. Illustrated
4th Edition. Ed: JH Dirckx, M.D. 2001.Lippincott Williams &
Wilkins.]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11860940&dopt=Abstract
Zhonghua Yu Fang Yi Xue
Za Zhi 2000 Nov;34(6):327-329
[Effects
of fluoride on the expression of c-fos
and c-jun genes and cell proliferation of rat osteoblasts]
[Article in Chinese]
Chen
L, Tong A, Yu D, et Al.
Department of Endocrinology,
Tongji Medical University, Wuhan 430022, China.
OBJECTIVE: To investigate the effects of sodium
fluoride (NaF) on the expression
of c-Fos and c-Jun genes and osteoblast cell proliferation of rat
osteoblasts.
METHODS: Osteoblastic cells were isolated from baby rat calvaria,
and cultured in the presence of different doses of NaF
(10(minus sign5) mol/L, 10(minus sign4) mol/L, and 10(minus sign3)
mol/L). Cell proliferation was measured by the MTT method, and c-Fos
and c-Jun expression was detected by the immunohistochemistry combined
with image analysis compute system.
RESULTS: RESULTS: from the MTT assay showed that NaF
increased the proliferation of rat osteoblast and induced the expression
of c-Fos and c-Jun genes. The increases of c-Fos and c-Jun expression
by the 3 different doses of NaF were
5.4%, 15.4% and 42.3% for the c-Fos gene and 12.1%, 14.4% and 38.6%
for c-Jun gene respectively (P < 0.05 and P < 0.01).
CONCLUSION: NaF increased
rat osteoblastic cell proliferation and the expression of genes
involved in cell proliferation.
PMID: 11860940 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8637511&dopt=Abstract
Mutat Res 1996
May;368(1):7-13
Clastogenic
activity of sodium fluoride to rat vertebral body-derived
cells in culture.
Mihashi
M, Tsutsui T.
Department of Pharmacology, School of Dentistry at Tokyo, Nippon
Dental University, Japan.
The US National Toxicology Program has shown equivocal evidence
of carcinogenic activity of sodium fluoride
(NaF) in male F344/N rats based on
the occurrence of five osteosarcomas in treated animals. In the
study the osteosarcomas developed mainly in the rat vertebrae. To
provide a possible mechanistic basis for the observed tumors, the
genotoxic effects of NaF on the possible
target organ of NaF carcinogenesis
were examined. Rat vertebral body-derived (RVBd) cells were established
from trabecular bone of vertebral bodies of a male F344/N rat 6
weeks of age and treated with NaF.
RVBd cells in secondary culture exhibited a high level of alkaline
phosphatase (ALP) activity when the cells at confluence were assayed
by ALP staining. When the histochemical examination was performed
on RVBd cell colonies, most of the colonies were stained positively
for ALP. Confluent RVBd cells were responsive to 10(-8) M 1 alpha.25-dihydroxyvitamin
D3 with a 7.7-fold increase in osteocalcin production over base
line values. The von Kossa staining demonstrated that in the presence
of 2 mM beta-glycerophosphate, RVBd cells that were allowed to grow
past confluence for approximately 2 months formed mineralized nodules.
When RVBd cells in tertiary culture were treated with
NaF at 0.5-2.0 mM for 24-72 h, the growth and/or survival
of the treated cells was reduced in a dose-dependent manner. Significant
increases in the frequencies of chromosome aberrations were induced
in a dose- and treatment time-dependent fashion when NaF
was administered to RVBd cells at 0.5 and 1.0 mM for 24 and 48 h.
The results indicate that NaF is genotoxic
to rat vertebrae, providing a possible mechanism for the vertebrae,
as a target organ of NaF carcinogenesis.
PMID: 8637511 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8770696&dopt=Abstract
J Bone Miner Res 1996
Jan;11(1):46-55
Aluminum
potentiates the effect of fluoride on tyrosine phosphorylation
and osteoblast replication in vitro and bone mass in vivo.
Caverzasio
J, Imai T, Ammann P, Burgener D, Bonjour JP.
Department of Medicine, University Hospital of Geneva, Switzerland.
Osteosclerosis in workers exposed to fluoride (F) and aluminum (Al)
(industrial fluorosis) led to the use of F as a treatment to increase
bone mass in osteoporosis patients. Because the influence of traces
of Al on the effects of F on bone formation is heretofore unknown,
we have investigated this issue both in vitro and in vivo. We have
found that minute amounts of Al (< or = 10(-5) M) potentiate
the effects of F in vitro such that osteoblast proliferation increased
by 15 +/- 2.7% at 50 microM (p < 0.001) and by 117.6 +/- 5.1%
at 750 microM (p < 0.001), concentrations of F with no mitogenic
effect alone. F + Al time-dependently modulated a growth factor
signaling pathway(s) associated with enhanced tyrosine phosphorylation
(TyrP) of several proteins (p90 [2.9x], p77 [4.9x], p68 [9.6x],
and mitogen activated protein kinases [3x]). TyrP was only slightly
or not at all changed by F and Al alone, respectively. The effects
of F + Al on TyrP and cell proliferation were markedly reduced by
100 microM tyrphostin-51, a tyrosine kinase inhibitor. Protein kinase
A (PKA) and protein kinase C (PKC) pathways were not involved in
this response. In vivo, F + Al administered for 8 months, at doses
that had no effect when the minerals were administered individually,
significantly enhanced proximal tibia bone mineral density (BMD)
by 6.3 +/- 1% compared with initial values and by 2-fold compared
with control ovariectomized rats (p < 0.0001). These
effects are consistent with a crucial role of Al in osteosclerosis
observed in industrial fluorosis. The results suggest that the combination
of F + Al modulates a growth factor-dependent TyrP pathway enhancing
mitogen-activated protein kinase and osteoblastic proliferation
and bone mass.
PMID: 8770696 [PubMed - indexed for MEDLINE]
|