Bone - Adverse Effects
Sodium fluoride

CAS No.
7681-49-4
 
 

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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
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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 prot
ein 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 m
utations, 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]

 
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