The biology of orthodontic tooth movement part 2: modulating tooth movement via nitric oxide and prostaglandin production

Dr. Michael S. Stosich reviews the markers of bone cell activity that are intrinsic to the complex process of bone modeling and remodeling

Modulation of bone for orthodontic tooth Movement

In the ever complex process of bone mod-eling and remodeling, certain markers of bone cell activity have been shown to act as key players that in part govern the process. Nitric oxide (NO) and prostaglandin (PGE²) production have been used as parameters in bone cell mechanosensitivity in the study of bone remodeling. Turner, et al.,¹ have shown that NO and PGE² act as mediators in the bone formation process in vivo. Loading bone cells mechanically is also associated with an increased production of PGE².² When nitric oxide synthase (iNOS) is inhibited, the loading response in bone ceases.³ This indicates the essential role of NO in the early stages of bone remodeling.

The production of NO and PGE² by primary bone cells is dependent upon applied stress. Bone cells might detect mechanical signals through fluid flow, and mechanical loading of bone causes flow of interstitial fluid through the canalicular network.⁴ Using cyclic strains, PGE² nor NO could be detected; however, under low levels of fluid flow, rapid production of both agents was induced.⁴ Bone cells treated with pulsating fluid flow (PFF) of increasing flow rate rapidly stimulate the production of NO in a manner that is dose dependent.⁵ PGE² production tended to be higher as a result of increased shear stress on the cells, which was achieved by increasing the flow rate.⁵ These results offer sound evidence for the importance of shear stress as a stimulus on bone cell walls in the process of bone cell mechanotransduction remodeling.

Ultrasound stimulates NO and PGE² production of human osteoblasts

Reher, et al.,⁶ have shown that in bone repair both osteogenesis and angiogenesis are essential, and it has been shown that the therapeutic range of ultrasound stimulates bone formation and osteoblast proliferation, and stimulates the synthesis of angiogenic factors, endothelial growth factors, basic fibroblast growth factors, and interleukin-8. The ultrasound may in fact act like mechanical stress on the bone and stimulate PGE² and NO production, which are essential for bone remodeling. NO production in bone showed a marked increase when treated with 45 kHz of therapeutic ultrasound.

Furthermore, iNOS and L-NAA had an inhibitory effect on the ultrasound therapy. Similarly, higher levels of PGE² were detected when the bone was subjected to ultrasound, and COX-2 inhibited PGE² synthesis at a frequency of 45 kHz. These results show that when bone is subjected to a therapeutic range of ultrasound, osteoblasts are stimulated to produce NO and PGE². The synthesis of PGE2 appears to be promoted by the inducible cycloxygenase pathway (COX-2). It may also be inferred that L-arginine is crucial in the NO pathway.

It has been shown that NO and PGE² are essential in the bone remodeling process. The studies here support the idea that varying forms of mechanical therapy, be it from shear stress or ultrasound, elucidate a prominent increase in NO and PGE² activity, which may in turn lead to new possibilities for increasing turnover time in bone remodeling, and potentially more rapid orthodontic tooth movement.

References

1. Turner CH, Owan I, Jacob DS, McClintock R, Peacock M. Effects of nitric oxide synthase inhibitors on bone formation in rats. Bone. 1997;21(6):487-490.

2. Binderman I, Zor U, Kaye AM, Shimshoni Z, Harell A, Sömjen. The transduction of mechanical force into biochemical events in bone cells may involve activation of phospholipase A2. Calcif Tissue Int. 1988;42(4):261-266.

3. Fox SW, Chambers TJ, Chow, JW. Nitric oxide as an early mediator of the increase in bone formation by mechanical stimulation. Am J  Physiol. 1996;270(6 Pt 1):E955-E960.

 4. Smalt R, Mitchell FT, Howard RL, Chambers TJ. Mechanotransduction in bone cells: induction of nitric oxide and prostaglandin synthesis by fluid shear stress, but not by mechanical strain. Adv Exp Med Biol. 1997;433:311-314.

5. Bakker AD, Soejima K, Klein-Nulend J, Burger EH. The production of nitric oxide and prostaglandin E(2) by primary bone cells is shear stress dependent. J Biomech.2001;34(5):671-677.

6. Reher P, Harris M, Whiteman M, Hai HK, Meghji S. Ultrasound stimulates nitric oxide and prostaglandin E2 production by human osteoblasts. Bone. 2002;31(1):236-241.