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Macrophage-Colony Stimulating Factor (M-CSF) is critical for osteoclast differentiation and development. It has been previously observed that M-CSF administration and over-expression in mice causes an increase in cortical bone formation. We hypothesize that M-CSF increases osteoblast activity indirectly via coupling of these two bone cells. This study examined the impact on bone properties of relatively low doses of M-CSF in mice. Four groups of seven-week old C57BL/6J mice were used: (1) baseline controls, (2) placebo controls, (3) 10 micrograms/kg/day M-CSF, (4) 100 micrograms/kg/day M-CSF. Injections were administered daily for the 21-day study. Three bone labels of calcein and tetracycline were alternately administrated (days 0, 9 and 18) to allow quantification of new bone formation. MicroCT scans (15 micron resolution) were performed on the proximal end of the right tibiae (1.0 mm section of trabecular bone) and left femur mid-diaphysis (0.25 mm cortical section). Dry mass, mineral content and percent mineral composition were obtained from the left tibiae. Functional changes were not detected in the bones of the mice receiving low doses of M-CSF. In particular, as previous studies have reported in mice receiving high doses of M-CSF or transgenic mice overexpressing bone specific M-CSF, changes to cortical bone did not occur with the lower doses. This may indicate that high doses of M-CSF and/or longer periods of administration may be required to observe the anabolic effect of M-CSF on mouse cortical bone.

The objective of this study was to examine changes in the long bones of male C57BL/6J mice with growth and aging, and to consider the applicability of this animal for use in studying Type II osteoporosis. Male C57BL/6J mice were aged in our colony between 4 and 104 weeks (n=9-15/group). The right femur and humeri were measured for length and subjected to mechanical testing (3-point flexure) and compositional analysis. The left femurs were embedded and thick slices at the mid-diaphysis were assessed for morphology, formation indices, and bone structure. In young mice, rapid growth was marked by substantial increases in bone size, mineral mass, and mechanical properties. Maturity occurred between 12 and 42 weeks of age with the maintenance of bone mass and mechanical properties. From peak levels, mice aged for 104 weeks experienced decreased whole femur mass (12.1 and 18.6% for dry and ash mass, respectively), percentage mineralization (7.4%), diminished whole bone stiffness (29.2%), energy to fracture (51.8%), and decreased cortical thickness (20.1%). Indices of surface-based formation decreased rapidly from the onset of the study. However, the periosteal perimeter and, consequently, the cross-sectional moments of inertia continued to increase through 104 weeks, thus maintaining structural properties. This compensated for cortical thinning and increased brittleness due to decreased mineralization and stiffness. The shape of the mid-diaphysis became increasingly less elliptical in aged mice, and endocortical resorption and evidence of subsequent formation were present in 20-50% of femurs aged > or =78 weeks. This, combined with the appearance of excessive endocortical resorption after 52 weeks, indicated a shift in normal mechanisms regulating bone shape and location, and was suggestive of remodeling. The pattern of bone loss at the femoral mid-diaphysis in this study is markedly similar to that seen in cortical bone in the human femoral neck in Type II osteoporosis. This study has thus demonstrated that the male C57BL/6J mouse is a novel and appropriate model for use in studying endogenous, aging-related osteopenia and may be a useful model for the study of Type II osteoporosis.

We investigated the effect of major histocompatibility complex class II (MHC II) knockout on the development of the mouse peripheral skeleton. These C2D mice had less skeletal development at 8, 12 and 16 weeks of age compared to wild-type C57BL/6J (B6) male mice. The C2D mice had decreased femur mechanical, geometric and compositional measurements compared to wild type mice at each of these ages. C2D femur stiffness (S), peak force in 3-pt bending (Pm), and mineral mass (Min-M) were 74%, 64% and 66%, respectively, of corresponding B6 values at 8 weeks of age. Similar differences were measured at 12 weeks (for which C2D femoral S, Pm and Min-M were 71%, 72% and 73%, respectively, of corresponding B6 values) and at 16 weeks (for which C2D femoral S, Pm and Min-M were 80%, 66% and 61%, respectively, of corresponding B6 values). MHC II knockout delays the development of adult bone properties and is accompanied by lower body mass compared to wild-type controls.