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Sclerostin antibody (Scl-Ab) and parathyroid hormone (PTH) are bone-forming agents that have different modes of action on bone, although a study directly comparing their effects has not been conducted. The present study investigated the comparative quantitative effects of these two bone-forming agents over time on bone at the organ, tissue, and cellular level; specifically, at the level of the osteoblast (Ob) lineage in adolescent male and female rats. Briefly, eight-week old male and female Sprague-Dawley rats were administered either vehicle, Scl-Ab (3 or 50mg/kg/week subcutaneously), or human PTH (1-34) (75 μg/kg/day subcutaneously) for 4 or 26 weeks. The 50mg/kg Scl-Ab and the PTH dose were those used in the respective rat lifetime pharmacology studies. Using robust stereological methods, we compared the effects of these agents specifically at the level of the Ob lineage in vertebrae from female rats. Using RUNX2 or nestin immunostaining, location, and morphology, the total number of osteoprogenitor subpopulations, Ob, and lining cells were estimated using the fractionator or proportionator estimators. Density estimates were also calculated referent to total bone surface, total Ob surface, or total marrow volume. Scl-Ab generally effected greater increases in cancellous and cortical bone mass than PTH, correlating with higher bone formation rates (BFR) at 4 weeks in the spine and mid-femur without corresponding increases in bone resorption indices. The increases in vertebral BFR/BS at 4 weeks attenuated with continued treatment to a greater extent with Scl-Ab than with PTH. At 4 weeks, both Scl-Ab and PTH effected equivalent increases in total Ob number (Ob.N). Ob density on the formative surfaces (Ob.N/Ob.S) remained similar across groups while mineral apposition rate (MAR) was significantly higher with Scl-Ab at week 4, reflecting an increase in individual Ob vigor relative to vehicle and PTH. After 26 weeks, Scl-Ab maintained BFR/BS with fewer Ob and lower Ob.N/Ob.S by increasing the Ob footprint (bone surface area occupied by an Ob) and increasing MAR, compared with PTH. The lower Ob.N and Ob.N/Ob.S with Scl-Ab at 26 weeks were associated with decreased osteoprogenitor numbers compared with both vehicle and PTH, an effect not evident at week 4. Osteoprogenitor numbers were generally positively correlated with Ob.N across groups and timepoints, suggesting dynamic coordination between the progenitor and Ob populations. The time-dependent reductions in subpopulations of the Ob lineage with Scl-Ab may be integral to the greater attenuation or self-regulation of bone formation observed at the vertebra, as PTH required more Ob at the formative site with correlative increased numbers of progenitors compared with Scl-Ab indicating potentially greater stimulus for progenitor pool proliferation or differentiation.

AIM 11 beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is considered to contribute to the aetiology of the metabolic syndrome, and specific inhibitors have begun to emerge as treatments for insulin resistance and other facets of the syndrome, including atherosclerosis. Given the role of glucocorticoids and 11beta-HSD1 in the anti-inflammatory response and the involvement of inflammation in the development of atherosclerosis, 11beta-HSD1 inhibition may exacerbate atherosclerosis. Our aim was to investigate in vivo the effects of a specific 11beta-HSD1 inhibitor (2922) on atherosclerosis while assessing glucose homeostasis. METHODS We conducted a 12-week study administering 2922 (at three doses, 3, 10 and 100 mg/kg body weight) in Ldlr 3KO (Ldlr(-/-)Apob(100/100)Lep(ob/ob)) mice, a genetic model of obesity, insulin resistance, dyslipidaemia and atherosclerosis. Rosiglitazone and simvastatin were used to test the responsiveness of our model in both types of therapy. RESULTS 2922 was effective in reducing 11beta-HSD1 activity in inguinal adipose tissue (>90% for 100 mg/kg) and was efficacious in improving glucose homeostasis at doses > or =10 mg/kg. Plasma insulin, blood glucose, glucose tolerance and homeostatic model assessment indices were all improved in mice treated with 2922 (100 mg/kg) compared with control animals. Despite an improvement in these parameters, no differences were observed in body weight, adipose or lean tissue masses in the 2922-treated mice. Interestingly, circulating lipids, proinflammatory cytokines and atherosclerosis were unaltered in response to 2922, although a small reduction in LDL cholesterol was detected. CONCLUSIONS Importantly, 11beta-HSD1 inhibition leads to improved glucose metabolism and does not result in a worsening of atherosclerotic lesion area, yet retained antidiabetic potential in the face of multiple severe metabolic aberrations. This study reinforces the potential use of 11beta-HSD1 inhibitors in patients with the metabolic syndrome without negatively impacting atherosclerosis.