PubMed Health⌕ Search

Biomedical subjects

D M Cullen

Publications and source records attributed to D M Cullen.

24 records · Page 2Linked to original sources

Bone response to in vivo mechanical loading in C3H/HeJ mice.

Bone, being sensitive to mechanical stimulus, adapts to mechanical loads in response to bending or deformation. Although the signal/receptor mechanism for bone adaptation to deformation is still under investigation, the mechanical signal is related to the amount of bone deformation or strain. Adaptation to changes in physical activity depends on both the magnitude of increase in strain above average daily levels for maintaining current bone density and the Minimum Effective Strain (MES) for initiating adaptive bone formation. Given the variation of peak bone density that exists in any human population, it is likely that variation in levels for MES is, to a considerable degree, inherited and varies among animal species and breeds. This study showed a dose-related periosteal response to loading in C3H/HeJ mice. The extent of active formation surface, the rate of periosteal bone formation, and area of bone formation increased with increasing peak periosteal strain. In these mice, the loaded tibia consistently showed lower endocortical formation surface and mineral apposition rate than the nonloaded bones at every load level. Although periosteal expansion is the most efficient means of increasing moment of inertia in adaptation to bending, a dose response increase in endocortical formation would have been predicted. Our characterization of the mouse bone formation response to increasing bending loads will be useful in the design of experiments to study the tibial adaptive response to known loads in different mouse breeds.

Animals↗

Long-term effects of nicotine on bone and calciotropic hormones in adult female rats.

This study determined the effects of nicotine on serum concentrations of several calciotropic hormones, and bone formation and resorption end-points in 7 month old, adult female rats. Animals were administered either saline (n= 9/group), low dose nicotine at 3.0 mg/kg/day (n=10/group) or high dose nicotine at 4.5 mg/kg/day (n=11/group) by subcutaneous osmotic minipumps. At the end of a three months treatment period, serum concentrations of calcium, phosphorus, parathyroid hormone, calcitonin, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were determined. Femora, tibiae, and lumbar vertebrae (3-5) were collected and bone parameters evaluated included mineral density and content (femora and vertebrae), strength (femora and vertebrae) and histomorphometry (tibiae). Animals given nicotine had significantly lower levels of 25-hydroxyvitamin D than controls [20.8+/-1.4 ng/ml for the low dose group and 20.7+/-1.0 ng/ ml for the high dose group versus 27.6+/-1.3 ng/ml for the control group (mean+/-S.E.M.), P<0.01]. The high dose nicotine group had smaller vertebral areas (5.4+/-0.2 mm2 versus 6.2+/-0.2 mm2, P<0.05) and a lower bone mineral content than the controls (0.024+/-0.001 g versus 0.030+/-0.001 g, P<0.05). Tibial endocortical mineral apposition rate was also significantly lower in the high dose nicotine group than in the control group (1.06+/-0.13 microm/day versus 1.42+/-0.08 microm/day. P<0.05). No significant treatment differences were detected in bone density, cancellous bone histomorphometry, or bone strength. Results from the present study suggest that nicotine administration may adversely affect bone formation and decrease body storage of vitamin D.

Animals↗

Bone response to in vivo mechanical loading in two breeds of mice.

We investigated the bone response to external loading in C57BL/6J and C3H/HeJ mice, both breeds with low and high bone density, respectively. An in vivo tibial four-point bending device previously used for application of measured external loads in rats was adapted for mice. It delivered a uniform medio-lateral bending moment to the region of the tibia located 1-5.5 mm proximal to the tibio-fibula junction. The right legs of six C57BL/6J [low bone density (LBD)] and C3H/HeJ [high bone density (HBD)] mice were externally loaded in the device for 36 cycles/day at 2 Hz, 6 days/week for 2 weeks at 9.3 +/- 0.9 N force, inducing estimated lateral periosteal surface compressive strains of 5121 +/- 1128 mu epsilon in C3H/HeJ (HBD) mice (n = 6), significantly higher than the estimated 3988 +/- 820 mu epsilon in C57BL/6J mice (n = 6) (mean +/- SD). In addition, C3H/HeJ HBD mice (n = 11) were externally sham (pad pressure or no bending) loaded in the device for 36 cycles/day at 2 Hz, 3 days/week for 3 weeks at 9.3 +/- 0.9 N force. Calcein injections for bone labeling were given at the 10th and 3rd days before sacrifice. At the end of the experiment, all mice were killed and both tibiae were removed, fixed, embedded, and cross-sectioned through the loaded region. Both tibiae were measured for marrow area (Ma.Ar), cortical area (Ct.Ar), total area (Tt.Ar), cross-sectional moment of inertia (CSMI), and periosteal and endocortical woven bone surface (Wo.B/BS), single-labeled surface (sLS), double-labeled surface (dLS), and total formation surface (FS/BS). Differences in all variables due to breed and loading (both bending and sham-bending) were tested by two-way analysis of variance (ANOVA) (P < 0.05). Ma.Ar, Tt.Ar, and CSMI were greater in C57BL/6J (LBD) than in C3H/HeJ (HBD) mice. Periosteal and endocortical woven bone and formation surface were increased significantly more by loading (bending) in C57BL/6J than in C3H/HeJ mice. Periosteal woven bone response due to sham-bending or sham-loading was significantly lower than due to bending loads in the C3H/HeJ mice. We conclude that the bone response to external loading is greater in LBD mice than in HBD mice. The high bone density of C3H/HeJ (HBD) mice is related to breed-specific factors other than the response to loading.

Analysis of Variance↗

Time course of osteoblast appearance after in vivo mechanical loading.

The time course of the bone cellular response to mechanical loading is important in the design of optimal exercise prescriptions. This study examined the time course of periosteal cellular changes in the rat tibia following a single exposure of mechanical loading in four-point bending. The right tibiae of adult female Sprague Dawley rats (n = 48, 346 +/- 29 g) were loaded at 40 N (2000 mu epsilon) for 36 cycles at 2 Hz. Right loaded (L) and left nonloaded (NL) tibiae were collected on days 1, 2, 3, 4, 6, and 9 after loading. Cross sections from the loaded region were examined for periosteal differences in bone lining cell surface length, osteoblast surface length, and both alkaline phosphatase-positive cell surface length and width in the cellular layer. A single loading session increased osteoblast surface length as early as day 2, with a peak in expression on day 3. Nine days after a single loading session osteoblast surface length was not different from nonloaded control levels. Alkaline phosphatase width in the cellular periosteum was elevated by day 2 and remained elevated through day 9. This study shows the transient increase in osteoblast surface following a single loading session. It provides fundamental information regarding the timing of osteoblast appearance and the longevity of the response following mechanical stimulation.

Alkaline Phosphatase↗

Prostaglandin E2 increases the skeletal response to mechanical loading.

The study tested the influence of prostaglandin E2 (PGE2) on the skeletal response to increased in vivo mechanical loading through a four-point bending device. One hundred and twenty Sprague-Dawley female rats (6 months old, 354 +/- 34 g) were divided into 12 groups to accommodate all possible combinations of doses of loads (25, 30, or 35 N) and PGE2 (0, 0.1, 0.3, or 1 mg/kg). Rats received subcutaneous injections of PGE2 daily and in vivo loading of the right tibia every Monday, Wednesday, and Friday for four weeks. Histomorphometric analysis of the periosteal and endocortical surfaces following in vivo dual fluorochrome labeling was performed on both the loaded region of the right tibial diaphysis and a similar region of the left tibial diaphysis. Without PGE2, the threshold for loading to stimulate bone formation was 30 N (peak strain 1360 mu epsilon) at the periosteal surface and 25 N (peak strain 580 mu epsilon) at the endocortical surface. Without loading, the minimum dose of PGE2 to stimulate bone formation at all surfaces was 1 mg/kg/day. When 1 mg/kg/day PGE2 was combined with the minimum effective load, an additive effect of PGE2 and loading on bone formation was observed at the endocortical surface, but a synergistic effect was noted at the periosteal surface. No combined effect of ineffective doses of loading and PGE2 was found. A synergistic effect at peak strains of approximately 1625 mu epsilon on the periosteal surface could suggest either the involvement of locally produced growth factors or autoregulation of endogenous synthesis of PGE2 by exogenously administered PGE2.

Animals↗

Cancellous bone behavior in hindlimb immobilized rats during and after naproxen treatment.

Temporary immobilization creates bone loss. The purpose of this investigation was to use an agent to protect the skeleton from bone loss bone during temporary immobilization. Eighty-nine 6-month-old retired breeder Sprague-Dawley female rats were used. Animals were randomly divided into six groups of equal numbers. Four groups were given drinking water from day 0, containing naproxen (100 or 200 mg/l). At day 7, half the animals in all groups had their right hindlimb immobilized. At day 49, half the immobilized rats and non-immobilized controls were sacrificed. The remaining rats were remobilized and the drug was stopped. At day 91, all remaining rats were sacrificed. Gastrocnemius and soleus muscle weights were determined. Right tibiae were analyzed for cancellous bone mass, bone structural and bone dynamic variables. At the close of immobilization, bone mass was lower in the right (immobilized) hindlimb of the immobilized group than in the non-immobilized group. Immobilized rats drinking 100 mg/l naproxen water had significantly higher bone mass in their immobilized limbs than did untreated immobilized rats, but all rats drinking 200 mg/l naproxen water had lower bone mass than controls. After 6 weeks of recovery, bone mass in the immobilized limb of untreated formerly immobilized rats improved, but remained below untreated never-immobilized rats. Formerly immobilized rats that had been treated with 100 mg/l naproxen water had normal bone mass after 6 weeks of recovery. Naproxen, an agent that mildly depresses activation frequency, prevents some of the transient bone mass and structural deterioration during temporary immobilization. Such treatment facilitates a more rapid return to normal bone mass, though not to normal structure. The more rapid recovery occurs because the difference from normal is less, not because of more rapid formation in recovering animals.

Analysis of Variance↗