Summation - Fluoride & Osteoblasts:

It is well known that fluoride can stimulate the production of new bone, albeit bone of inferior quality.

Fluoride induces the production of new bone, in part, by stimulating the proliferation of osteoblasts (bone forming cells). In addition to stimulating osteoblasts, fluoride may also induce toxic effects on osteoblasts. The difference between fluoride stimulation and toxicity is currently subject to debate.

Also, the question of how fluoride can stimulate the proliferation of osteoblasts is still unresolved. Some believe that fluoride stimulates osteoblasts by forming complexes with aluminum which in turn activate G-proteins in the cell, while others believe that fluoride stimulates osteoblasts by amplifying the effect of growth factors like IGF.

Excerpts from the Scientific Literature - Fluoride: Stimulation of Osteoblasts: (back to top)

"Studies in vitro suggested that the increased (bone) formation may be due to a direct effect of fluoride in stimulating osteoblast proliferation."
SOURCE: Lundy MW, et al. (1995). Histomophometric analysis of iliac crest bone biopsies in placebo-treated versus fluoride-treated subjects. Osteoporosis International 5:115-129.

"The anabolic effect of fluoride therapy is dependent on its cellular effects on the osteoblast lineage."
SOURCE: Boivin G, et al. (1993). Relationship between bone fluoride content and histological evidence of calcification defects in osteoporotic women treated long term with sodium fluoride. Osteoporosis International 3:204-208.

"The fluorotic group had a greater number of osetoblasts than controls with a very high proportion of flat osteoblasts (as compared to plump osteoblasts)."
SOURCE: Boivin G, et al. (1989). Skeletal fluorosis: histomorphometric analysis of bone changes and bone fluoride content in 29 patients. Bone 10:89-99.

"Stimulatory effects of fluoride on osteoblasts result in formation of osteoid, which subsequently undergoes mineralization."
SOURCE: Fisher RL, et al. (1989). Endemic fluorosis with spinal cord compression. A case report and review. Archives of Internal Medicine 149: 697-700.

"on the periosteal surfaces, the total number of osteoblasts is increased resulting in a cell-rich periosteum."
SOURCE: Ream LJ. (1983). Scanning electron microscopy of the rat femur after fluoride ingestion. Fluoride 16: 169-174.

"It would appear that fluoride may stimulate osteoblastic activity in bone, and the presence of uncalcified bone depends on the efficiency with which this is subsequently mineralized."
SOURCE: Jowsey J, et al. (1968). Some results of the effect of fluoride on bone tissue in osteoporosis. Journal of Clinical Endocrinology 28:869-874.

"Persistent high fluoride ingestion has been reported to produce a stimulation of osteoblastic activity, usually accompanied by an increased rate of bone resorption."
SOURCE: Cohen MB, Rubini ME. (1965). The treatment of osteoporosis with sodium fluoride. Clinical Orthopaedics 40: 147-152.

"In the fluoride-treated animals at 60 and 90 days, there was evidence of increase in the number of osteoblasts in productive areas. On the other hand, osteoclasts were also more numerous."
SOURCE: Belanger LF, et al. (1958). Rachitomimetic effects of fluoride feeding on the skeletal tissues of growing pigs. American Journal of Pathology 34: 25-36.

Excerpts from the Scientific Literature - Fluoride: Poisoning of Osteoblasts? (back to top)

"The increased amount of trabecular bone in fluoride therapy is claimed to be the morphologic expression for fluoride as a stimulus for bone formation. We propose that the increased amount of trabecular bone results from pathological bone formation by injured osteoblasts and decreased bone resorption by resorbing osteocytes and osteoclasts."
SOURCE: Krook L, Minor RR. (1998). Fluoride and alkaline phosphatase. Fluoride 31: 177-182.

"though the osteoblasts in fluoride-affected bone are active, there are fewer plump, cuboidal, highly secretory osteoblasts, suggesting that, whereas fluoride is mitogenic to osteoblastic precursors, it is toxic to individual osteoblasts at the same concentration."
SOURCE: Chachra D, et al. (1999). The effect of fluoride treatment on bone mineral in rabbits. Calcified Tissue International 64:345-351.

In fluoride-treated rats there was a "tendency for the mineral apposition rate to decrease and for the osteoid maturation time to increase, suggesting that a toxic effect on osteoblast function or on mineralization had occurred.... At the tissue level mineralized bone formation rate tended to fall, indicating that the inhibition of osteoblast function had outweighed the stimulatory effect on osteoblast proliferation."
SOURCE: Ittel TH, et al. (1992). Effect of fluoride on aluminum-induced bone disease in rats with renal failure. Kidney International 41: 1340-1348.

"Long-term effects of fluoride may include decreases in the life span and number of bone cells rather than a persistent hypercellurarity of bone forming cells."
SOURCE: Ittel TH, et al. (1992). Effect of fluoride on aluminum-induced bone disease in rats with renal failure. Kidney International 41: 1340-1348.

"Skeletal fluorosis is thus characterized by an unbalanced coupling in favor of bone formation, and a great number of osteoblasts with a high proportion of flat osteoblasts. This may explain the mineralization impairment proven by thick osteoid seams and reduced mineral apposition rate, and supports the view that fluoride may have a dual effect on osteoblasts: a probable increased birthrate at the tissue-level due to a mitogenic effect of fluoride on precursors of osteoblasts, and a toxic effect at the individual cell-level. The addition of these two effects represents, however, a marked increase of bone formation at the organ level."
SOURCE: Boivin G, et al. (1989). Skeletal fluorosis: histomorphometric analysis of bone changes and bone fluoride content in 29 patients. Bone 10:89-99.

"There is some evidence that fluoride at high concentrations may exert a toxic effect on osteoblast function. Following a long-term exposure to fluoride, especially at high doses, osteoblasts assume a flat, inactive appearance... Following long-term exposure to fluoride, the amount of osteoid surfaces covered by osteoblasts are decreased, suggestive of reduced osteoblastic activity. "
SOURCE: Pak CY. (1989). Fluoride and osteoporosis. Proceedings of the Society for Experimental Biology and Medicine 191: 278-86.

"one possible mode of action of NaF may be that, initially, its administration may stimulate osteoblasts to produce more bone in relation to bone removed by osteoclasts. However, within a short time interval, toxic effects may begin to appear and thus result in the observed decreases in bone formative activity. Since osteoclasts are also affected by NaF administration, with a longer passage of time, further increases in bone mass may not occur. The preservation of existing bone mass may be attributable to decreases in numbers of bone cells, in their functional efficiencies, and in their individual life-spans resulting presumably from cellular toxic effect of NaF."
SOURCE: Snow GR, Anderson C. (1986). Short-term chronic fluoride administration and trabecular bone remodeling in beagles: a pilot study. Calcified Tissue International 38: 217-221.

"osteoblasts that survive as osteocytes are visibly abnormal."
SOURCE: Riggs BL. (1983). Treatment of osteoporosis with sodium fluoride: An appraisal. Bone and Mineral Research 2: 366-393.

"The osteoblasts were atrophic in the present material."
SOURCE: Krook L, Maylin GA. (1979). Industrial fluoride pollution. Chronic fluoride poisoning in Cornwall Island cattle. Cornell Veterinarian 69(Suppl 8): 1-70.

"cytologic abnormalities found in osteoblasts."
SOURCE: Baylink DJ, Bernstein DS. (1967). The effects of fluoride therapy on metabolic bone disease. Clinical Orthopaedics and Related Research 55: 51-85.

"Mottling and osteomalacia were associated with changes in the osteoblasts. On moderate levels, osteoblasts that survived were abnormal, as seen in mottling. On a high fluoride levels, the osteoblasts were devoid of demilunes, spindled or very pyknotic."
SOURCE: Johnson LC. (1965). Histogenesis and mechanisms in the development of osteofluorosis. In: H.C.Hodge and F.A.Smith, eds : Fluorine chemistry, Vol. 4. New York, N.Y., Academic press (1965) 424-441.

Excerpts from the Scientific Literature - Fluoride & Osteoblasts: Mechanism of Action (back to top)

"The mechanism whereby NaF acts to stimulate bone cell proliferation and differentiation is controversial in that there are currently two major competing models, both of which involve activation of mitogen-activated protein kinase (MAPK). On the one hand, we postulated that NaF, at osteogenic concentrations, inhibits a fluoride-sensitive protein-tyrosine phosphatase in osteoblasts, resulting in the sustained increase of protein-tyrosine phosphorylation of key signaling proteins of the MAPK mitogenic pathway. This would then lead to the potentiation of bone cell proliferation initiated by growth factors. On the other hand, Caverzasio et al. proposed an alternate model in which NaF acts through the formation of the fluoroaluminate ion (AlF4) with the aluminum ion. The AlF4 ion would then activate a pertussis toxin-sensitive heterotrimeric Go/i protein, leading to an activation of certain cellular protein-tyrosine kinases. This, in turn, would increase the tyrosine phosphorylation of key signaling proteins of the MAPK signaling pathway, subsequently leading to increased osteoblast proliferation."
SOURCE: Lau KH, et al. (2002). Bone cell mitogenic action of fluoroaluminate and aluminum fluoride but not that of sodium fluoride involves upregulation of the insulin-like growth factor system. Bone 30: 705–711.

"these findings do not support the contention that the molecular mechanism of the bone cell mitogenic action of NaF is mediated primarily through the formation of the AlF4 ion."
SOURCE: Lau KH, et al. (2002). Bone cell mitogenic action of fluoroaluminate and aluminum fluoride but not that of sodium fluoride involves upregulation of the insulin-like growth factor system. Bone 30: 705–711.

"The first observation that fluoride can directly influence the activity of osteoblastic cells in culture was provided by Farley and coworkers in 1983. They showed that micromolar concentrations of fluoride increased the proliferation and alkaline phosphatase activity of bone cells dervied from chick embryonic calvaria... Similar observations were then reported by the same group in human bone cells derived from the trabecular bone of femoral head samples obtained during hip replacement. Following these initial observations, the in vitro effects of fluoride on osteoblastic cells were investigated in several laboratories. However, it became apparent that the in vitro effects of fluoride on cultured osteoblasts were difficult to reproduce in similar or other cultured osteoblast-like systems. Two laboratories reported their negative results on the direct effect of fluoride on human osteoblastic proliferation. From these negative results... it was concluded that, in vivo, fluoride may either act indirectly through the local synthesis of some growth factors or exerts a preferential action on a subpopulation of osteoblastic cells. In favor of the latter hypothesis, it has been suggested that osteoblast precursors are more sensitive to fluoride action than mature osteoblasts. The possibility that in vivo the effect of fluoride would be mediated by a cofactor has also been evoked."
SOURCE: Caverzasio J, et al. (1998). Fluoride: mode of action. Bone 22: 585-589.

"It was found that aluminum is an important cofactor for the expression of the mitogenic effect of fluoride in osteoblast-like cells... In the presence of traces of aluminum, fluoride concentrations close to those measured in plasma of osteoporotic patients treated with fluoride salts reproducibly enhanced cell proliferation. In vivo studies indicated that the combination of fluoride and aluminum was also more efficient than administration of each ion separately in increasing tibia bone mineral mass in the adult ovariectomized rats. These observations strongly suggested that a fluoroalumino complex is probably the active fluoride molecule responsible for the enhancement of the proliferation of bone-forming cells and the change in bone mineral mass in vivo."
SOURCE: Caverzasio J, et al. (1998). Fluoride: mode of action. Bone 22: 585-589.

"We propose that the increased amount of trabecular bone results from pathological bone formation by injured osteoblasts and decreased bone resorption by resorbing osteocytes and osteoclasts."
SOURCE: Krook L, Minor RR. (1998). Fluoride and alkaline phosphatase. Fluoride 31: 177-182.

"Mode of action as well as toxic events may be related to the inhibitory or activating effects of fluoride on a variety of cellular enzymes. It is of particular interest that aluminum forms strong complexes with fluoride which may participate in the spectrum of effects previously ascribed to fluoride. Since both ions are mainly excreted by the kidney, an impairment of excretory renal function should facilitate retention of fluoride and aluminum and may thus aggravate mutual effects."
SOURCE: Ittel TH, et al. (1992). Effect of fluoride on aluminum-induced bone disease in rats with renal failure. Kidney International 41: 1340-1348.

"These findings... provide additional support for our hypothesis that F stimulates osteoblast-line cell proliferation by potentiating the mitogenic actions of growth factors."
SOURCE: Lau KH, et al. (1989). A proposed mechanism of the mitogenic action of fluoride on bone cells: inhibition of the activity of an osteoblastic acid phosphatase. Metabolism 38:858-68.

"The mechanism by which fluoride stimulates osteoblasts is unclear. Both cellular and noncellular mechanisms have been suggested... Clearly, however, noncellular and cellular mechanisms are not mutually exclusive."
SOURCE: Riggs BL. (1983). Treatment of osteoporosis with sodium fluoride: An appraisal. Bone and Mineral Research 2: 366-393.

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