This dissertation examines the ability of insulin-like growth factor-I (IGF-I), macrophage colony stimulating factor (M-CSF), and osteoprotegerin (OPG) to ameliorate osteopenia affected by three disuse models. The three models are: spaceflight (IGF-I), tail suspension (IGF-I, M-CSF, OPG), and sciatic nerve crush (OPG). Mechanical testing, physical and compositional analyses, and quantitative hi stomorphometry are utilized to measure the effects of disuse and cytokine treatments.
For the spaceflight/IGF-I experiment, a previously unreported IGF-I induced inhibition of endocortical bone formation for the humerus and femur were discovered. This inhibition of bone formation occurred for spaceflight animals as well as ground controls, indicating that the mechanism for this inhibition was unrelated to mechanical loading. An unloading influenced resistance to IGF-1 efficacy was not observed as was reported to occur for tail suspension unloading.
The IGF-I and M-CSF tail suspension study had few significant results. The results observed in the spaceflight study with rats were not repeated in the tail suspension study with mice. There was a possible trend towards M-CSF increasing endocortical resorption and inhibiting periosteal formation.
Osteoprotegerin increased femoral mechanical properties of tail suspended mice to the degree that typical tail suspension effects on strength and stiffness were eliminated. OPG also caused an unexpected and unreported increase in percent mineral composition for femora, tibia and humerus for control and tail suspended groups (to the degree that p<0.001 for all comparisons). As expected, OPG decreased bone resorption. The decrease in resorption was not great enough to account for the increase in mechanical properties, indicating that the increase in mineral composition affected an increase in bone material properties.
OPG also increased percent mineral composition in the nerve crush study. This is important because the mice used for this study were nearly mature, suggesting that OPG may increase mineral composition in extant bone. Both the tail suspension and nerve crush OPG studies observed trends towards OPG decreasing endocortical formation. The effect OPG has on mineral composition and formation merit further investigation.
|1991||Bertram JEA, Swartz SM. The "law of bone transformation": a case of crying Wolff? Biol Rev. August 1991;66(3):245-273.|
|1978||Morey ER, Baylink DJ. Inhibition of bone formation during space flight. Science. September 22, 1978;201(4361):1138-1141.|
|1990||Evans GP, Behiri JC, Currey JD, Bonfield W. Microhardness and Young's modulus in cortical bone exhibiting a wide range of mineral volume fractions, and in a bone analogue. J Mater Sci Mater Med. June 1990;1(1):38-43.|
|1987||Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR. Bone histomorphometry: standardization of nomenclature, symbols, and units: report of the ASBMR histomorphometry nomenclature committee. J Bone Miner Res. December 1987;2(6):595-610.|
|1993||Broz JJ, Simske SJ, Greenberg AR, Luttges MW. Effects of rehydration state on the flexural properties of whole mouse long bones. J Biomech Eng. 1993;115(4A):447-449.|
|1996||Parfitt AM, Mundy GR, Roodman GD, Hughes DE, Boyce BF. A new model for the regulation of bone resorption, with particular reference to the effects of bisphosphonates. J Bone Miner Res. February 1996;11(2):150-159.|
|1984||Parfitt AM. The cellular basis of bone remodeling: the quantum concept reexamined in light of recent advances in the cell biology of bone. Calcif Tiss Int. March 1984;36(suppl 1):S37-S45.|
|1982||Martin RB, Burr DB. A hypothetical mechanism for the stimulation of osteonal remodelling by fatigue damage. J Biomech. 1982;15(3):137-139.|
|1995||Fleet ML. The Effect of Developmental Stage on the Mouse Response to Induced Osteopenia [PhD thesis]. University of Colorado; 1995.|
|1972||Chamay A, Tschantz P. Mechanical influences in bone remodeling: experimental research on Wolff's law. J Biomech. March 1972;5(2):173-180.|
|1986||Keller TS, Spengler DM, Carter DR. Geometric, elastic, and structural properties of maturing rat femora. J Orthop Res. 1986;4(1):57-67.|
|1998||Lacey DL, Timms E, Tan H-L, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, Hsu H, Sullivan J, Hawkins N, Davy E, Capparelli C, Eli A, Qian Y-X, Kaufman S, Sarosi I, Shalhoub V, Senaldi G, Guo J, Delaney J, Boyle WJ. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. April 17, 1998;93(2):165-176.|
|1987||Rubin CT, Lanyon LE. Osteoregulatory nature of mechanical stimuli: function as a determinant for adaptive remodeling in bone. J Orthop Res. 1987;5(2):300-310.|
|1981||Doty SB. Morphological evidence of gap junctions between bone cells. Calcif Tiss Int. 1981;33(5):509-512.|
|1992||Frost HM, Jee WSS. On the rat model of human osteopenias and osteoporoses. Bone Miner. September 1992;18(3):227-236.|
|1988||Currey JD. The effects of drying and re-wetting on some mechanical properties of cortical bone. J Biomech. 1988;21(5):439-441.|
|1969||Frost HM. Tetracycline-based histological analysis of bone remodeling. Calcif Tiss Res. 1969;3(1):211-237.|
|1990||Currey JD, Brear K. Hardness, Young's modulus and yield stress in mammalian mineralized tissues. J Mater Sci Mater Med. June 1990;1(1):14-20.|
|1990||Simske SJ. Development of Model Osteoporosis in Mice: Alleviation by Electromagnetics and Alternative Treatments [PhD thesis]. University of Colorado; July 1990.|