Genetic Variations in Bone Density, Histomorphometry, and Strength in Mice

The purpose of this study was to assess breed-related differences in bone histomorphometry, bone biomechanics, and serum biochemistry in three mouse breeds shown to differ in bone mineral density (BMD) (as measured by DXA) and bone mineral content (BMC). Femurs, tibiae, and sera were collected from 16-week-old C3H/HeJ {C3H}, C57BL/6J {BL6}, and DBA/2J {DBA}mice (n = 12/breed). Data collected included BMC and BMD (femora), histomorphometry of cancellous (distal femur) and cortical bone (diaphyseal tibiae and femora), bone strength (femora), and serum alkaline phosphatase (ALP). Consistent with previous reports, BMC and BMD were higher in C3H than in BL6 or DBA mice. The higher BMD in the C3H breed was associated with greater cancellous bone volume, cortical bone area, periosteal bone formation rate, biomechanical strength, and serum ALP. However, mid-diaphyseal total femoral and tibial cross-sectional area and moment of inertia were greatest in BL6, intermediate in C3H, and lowest in DBA mice. The specific distribution of cortical bone in C3H, BL6, DBA mice represents a difference in adaptive response to similar mechanical loads in these breeds. This difference in adaptive response may be intrinsic to the adaptive mechanism, or may be intrinsic to the bone tissue material properties. In either case, the bone-adaptive response to ordinary mechanical loads in the BL6 mice yields bones of lower mechanical efficiency (less stiffness per unit mass of bone tissue) and does not adapt as well as that of the C3H mice where the final product is a bone with greater resistance to bending under load. We suggest that the size, shape, and BMD of the bone are a result of breed-specific genetically regulated cellular mechanisms. Compared with the C3H mice, the lower BMD in BL6 mice is associated with long bones that are weaker because the larger cross-sectional area fails to compensate completely for their lower BMD and BMC. Received: 16 November 1999 / Accepted: 19 April 2000 / Online publication: 27 July 2000     

Effects of Nicotine on Bone and Calciotropic Hormones in Growing Female Rats

Limited research in young adults and immature animals suggests a detrimental effect of tobacco on bone during growth. This study investigated the effects of nicotine, the major alkaloid component of tobacco, on calciotropic hormone concentrations and bone status in growing female rats. One-month-old animals received either saline (n = 10), nicotine at 3.0 mg/kg/day (n = 10), or nicotine at 4.5 mg/kg/day (n = 10) administered subcutaneously via osmotic minipumps for either 2 or 3 months. Sera, femora, tibiae, and lumbar vertebrae (3–5) were collected at necropsy. The concentrations of serum calcium, phosphorus, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, parathyroid hormone, calcitonin, and insulin-like growth factor-I were determined. Bone variables evaluated included mineral content and density (vertebrae and femora), cancellous and cortical histomorphometry (tibiae), and bone strength (vertebrae and femora). Statistically significant differences in serum mineral and hormone concentrations were not associated with nicotine dose or exposure time. No significant nicotine treatment effects were detected for bone mineral content and density, bone histomorphometry, or bone strength. We conclude that nicotine treatment for 2 or 3 months at serum concentrations in the upper range of those found in smokers has no detrimental effect on bone mass, volume, or strength in the growing rat. Received: 20 May 1999 / Accepted: 21 January 2000     

Blood Pressure Recordings During Hemodialysis Access Interventions: Implications for Acute Management

A retrospective study evaluating the pattern of blood pressure and its related complications before, during, and after percutaneous hemodialysis interventions was performed in patients presenting with asymptomatic hypertension. Hemodialysis patients undergoing percutaneous interventions including tunneled hemodialysis catheter insertion, percutaneous balloon angioplasty and thrombectomy procedure, and stage II hypertension (systolic blood pressure ≥160 mmHg) were included in this analysis. Blood pressure medications were not used while midazolam and fentanyl were routinely administered. Patients were followed for up to 4 weeks to monitor any complications. The mean blood pressure before, during, and after the procedures were 185 ± 18/96 ± 14, 172 ± 22/92 ± 15, and 153 ± 25/87 ± 14, respectively. There was a statistically significant difference between the blood pressure readings before and after the procedure (before = 185 ± 18/96 ± 14, after = 153 ± 25/87 ± 14; p = 0.001). None of the patients had a stroke, myocardial infarction, or acute pulmonary edema before, during, or after the procedure or during the 4‐week follow‐up period. A significant reduction in blood pressure was observed after the procedure without the administration of any antihypertensive medication. These results suggest that the reduction in blood pressure observed after percutaneous dialysis access interventions (particularly in the presence of midazolam and fentanyl) may make it unnecessary to treat asymptomatic hypertension prior to these procedures.     

The drug-user husband and his wife: attachment styles,family cohesion,and adaptability

This study which assesses the association between the attachment styles of drug-user husbands (n = 56) and their wives (n = 56) and their perceptions of family dynamics was conducted in 1998. The population study included heroin (52.9%) and multidrug detoxified outpatients. All subjects completed the Adult Attachment Style Scale and the FACES III. Results indicated that the perceptions of family adaptability and cohesion among the drug-user husbands and their wives did not differ from the Israeli norm. Most of the drug users (60.7%) were characterized by the avoidant attachment style, followed by the secure style (26.8%), and the anxious/ambivalent style (12.5%). Half the wives (53.6%) were characterized by the secure style, followed by the avoidant style (42.9%) and the anxious/ambivalent style (3.6%). A secure style in husband and wife was associated with higher levels of family cohesion and adaptability, and the anxious/ambivalent style with a lower perception of family cohesion and adaptability. These findings have important implications for rehabilitation prospects and for planning intervention programs.     

Effects of voluntary wheel running on goserelin acetate-induced bone degeneration

A common treatment option for many breast and prostate cancer patients is the use of a luteinizing hormone-releasing hormone agonist such as goserelin acetate (GA) which reduces sex hormone levels. This treatment, however, is associated with bone degeneration, and exercise has been suggested as a means of preventing this side effect. Little is known about the effects of low intensity, low volume exercise on GA-induced bone loss. The purpose of this study, therefore, was to investigate the effects of voluntary wheel running on bone architecture in growing male (M) and female (F) rats receiving GA treatment. Rats received an 8-week GA treatment or placebo (CON) and were either housed in cages equipped with voluntary running wheels (WR) or remained sedentary (SED) in standard cages throughout the experimental period. Following treatments, tibiae were excised and analyzed for cortical bone (cross-sectional volume, cortical volume, marrow volume, cortical thickness) and cancellous bone (bone volume/total volume, trabecular number, trabecular thickness, trabecular spacing) using micro-computed tomography. Treatment with GA resulted in a significant reduction in running wheel distances in both sexes throughout the study period (P < 0.05). GA treatment had no effect on cortical bone architecture in neither sex (P > 0.05). Cancellous bone degeneration, however, was observed in M and F SED + GA (P < 0.05). No significant differences were observed in M WR + GA animals in bone volume/total volume, trabecular number and trabecular spacing when compared to M SED + CON (P > 0.05). In F WR + GA, trabecular thickness did not differ from that of F SED + CON (P > 0.05), and trabecular spacing was found to be significantly lower than F SED + GA (P < 0.05). The current report indicates that 8 weeks of GA treatment promotes cancellous bone degeneration, and voluntary wheel running provides no clear osteoprotection in growing male and female rats.     

Effects of Nicotine on Bone Mass, Turnover, and Strength in Adult Female Rats

This study investigated the effects of nicotine, the chemical responsible for tobacco addiction, on bone and on serum mineral and calcitropic hormone levels in adult, female rats to help resolve a current controversy regarding the impact of nicotine on bone health. Seven-month-old rats received either saline (n = 12), low-dose nicotine (4.5 mg/kg/day, n = 2), or high-dose nicotine (6.0 mg/kg/day, n = 12) administered subcutaneously via osmotic minipumps for 3 months. Blood, femora, tibiae, and lumbar vertebrae (3-5) were collected at necropsy for determination of serum mineral and hormonal concentrations, bone density (femora and vertebrae), bone turnover (tibiae), and bone strength (femora). The presence of nicotine in serum (111 +/- 7 and 137 +/- 10 ng/ml for the low- and high-dose nicotine groups, respectively) confirmed successful delivery of the drug via osmotic minipumps. Nicotine-induced treatment differences were not detected in serum calcium, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D. However, serum phosphorus and parathyroid hormone (PTH) were higher in rats treated with high-dose nicotine, and serum calcitonin was lower in rats treated with both high- and low-dose nicotine than in control rats. Nicotine treatment had no effect on tibial cancellous or cortical bone turnover or femoral bone mineral content (BMC) and density (BMD). Femoral ultimate load and vertebral BMC were lower in rats treated with high-dose nicotine than in control rats. We conclude that nicotine at serum concentrations 2.5-fold greater than the average in smokers has limited detrimental effects on bone in normal, healthy female rats.     

Differential down-regulation of D1-stimulated adenylate cyclase activity in rat forebrain after in vivo amphetamine treatments

Amphetamine has complex behavioral actions in the rat that depend upon the release of dopamine in striatal and mesolimbic brain regions. To explore a possible role of the dopamine-sensitive cAMP second-messenger system in mediating these effects, we examined the effects of in vivo amphetamine treatments on the D1 receptor-coupled adenylate cyclase system in membranes from striatal and mesolimbic rat brain regions. The results show that amphetamine produces a regional, dose- and time-dependent down-regulation of adenylate cyclase activity. Intermediate and high doses of amphetamine (2.5 and 7.5 mg/kg, respectively), but not a low dose (1.0 mg/kg), resulted in a decrease in the apparent Vmax and/or an increase in the apparent Ka for the selective D1 partial agonist, SKF38393, in striatal membranes 30 min after amphetamine treatment. Treatment of rats with 7.5 mg/kg amphetamine for 30 and 60 min, but not 10 min, similarly resulted in a down-regulation of D1-mediated adenylate cyclase activity in striatal membranes. In contrast, in mesolimbic tissues, no amphetamine treatment at any time resulted in an alteration of SKF38393-stimulated adenylate cyclase activity relative to saline controls. The results of behavioral analyses also showed that animals exhibiting intense stereotypies had significantly lower striatal apparent Vmax values than did those animals engaged in moderate or no behavioral activity at the time of decapitation. These findings demonstrate that amphetamine treatments result in a down-regulation of striatal, but not mesolimbic, dopamine-sensitive adenylate cyclase activity that parallels the intense, stereotyped behaviors characteristic of dopaminergic activation in the striatum.     

Metabolic Coupling Between Bone Marrow Adipose Tissue and Hematopoiesis

Purpose of Review

Mesenchymal stem cells (MSCs) located in the bone marrow have the capacity to differentiate into multiple cell lineages, including osteoblast and adipocyte. Adipocyte density within marrow is inversely associated with bone mass during aging and in some pathological conditions, contributing to the prevailing view that marrow adipocytes play a largely negative role in bone metabolism. However, a negative association between marrow adipocytes and bone balance is not universal. Although MAT levels appear tightly regulated, establishing the precise physiological significance of MAT has proven elusive. Here, we review recent literature aimed at delineating the function of MAT.

Recent Findings

An important physiological function of MAT may be to provide an expandable/contractible fat depot, which is critical for minimization of energy requirements for sustaining optimal hematopoiesis. Because the energy requirements for storing fat are negligible compared to those required to maintain hematopoiesis, even small reductions in hematopoietic tissue volume to match a reduced requirement for hematopoiesis could represent an important reduction in energy cost. Such a physiological function would require tight coupling between hematopoietic stem cells and MSCs to regulate the balance between MAT and hematopoiesis. Kit-ligand, an important regulator of proliferation, differentiation, and survival of hematopoietic cells, may function as a prototypic factor coupling MAT and hematopoiesis.

Summary

Crosstalk between hematopoietic and mesenchymal cells in the bone marrow may contribute to establishing the balance between MAT levels and hematopoiesis.