Cytokine Therapies for Short-Term Disuse Osteopenia Models in Murines

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.

Year	Entry
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1997	Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang M-S, Lüthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan H-L, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Sander S, Van G, Tarpley J, Derby P, Lee R, Boyle WJ; Amgen EST Program. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. April 18, 1997;89(2):309-319.
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Year

Entry

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.

1989

Keller TS, Spengler DM. Regulation of bone stress and strain in the immature and mature rat femur. J Biomech. 1989;22(11-12):1115-1127.

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.

1972

Chamay A, Tschantz P. Mechanical influences in bone remodeling: experimental research on Wolff's law. J Biomech. March 1972;5(2):173-180.

1997

Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang M-S, Lüthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan H-L, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Sander S, Van G, Tarpley J, Derby P, Lee R, Boyle WJ; Amgen EST Program. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. April 18, 1997;89(2):309-319.