11β-HSD1 plays a critical role in trabecular bone loss associated with systemic glucocorticoid therapy

Background: Despite their efficacy in the treatment of chronic inflammation, the prolonged application of therapeutic glucocorticoids (GCs) is limited by significant systemic side effects including glucocorticoid-induced osteoporosis (GIOP). 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a bi-directional enzyme that primarily activates GCs in vivo, regulating tissue-specific exposure to active GC. We aimed to determine the contribution of 11β-HSD1 to GIOP. Methods: Wild type (WT) and 11β-HSD1 knockout (KO) mice were treated with corticosterone (100 μg/ml, 0.66% ethanol) or vehicle (0.66% ethanol) in drinking water over 4 weeks (six animals per group). Bone parameters were assessed by micro-CT, sub-micron absorption tomography and serum markers of bone metabolism. Osteoblast and osteoclast gene expression was assessed by quantitative RT-PCR. Results: Wild type mice receiving corticosterone developed marked trabecular bone loss with reduced bone volume to tissue volume (BV/TV), trabecular thickness (Tb.Th) and trabecular number (Tb.N). Histomorphometric analysis revealed a dramatic reduction in osteoblast numbers. This was matched by a significant reduction in the serum marker of osteoblast bone formation P1NP and gene expression of the osteoblast markers Alp and Bglap. In contrast, 11β-HSD1 KO mice receiving corticosterone demonstrated almost complete protection from trabecular bone loss, with partial protection from the decrease in osteoblast numbers and markers of bone formation relative to WT counterparts receiving corticosterone. Conclusions: This study demonstrates that 11β-HSD1 plays a critical role in GIOP, mediating GC suppression of anabolic bone formation and reduced bone volume secondary to a decrease in osteoblast numbers. This raises the intriguing possibility that therapeutic inhibitors of 11β-HSD1 may be effective in preventing GIOP in patients receiving therapeutic steroids

Multilineage Potential of Stable Human Mesenchymal Stem Cell Line Derived from Fetal Marrow

Human bone marrow contains two major cell types, hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs). MSCs possess self-renewal capacity and pluripotency defined by their ability to differentiate into osteoblasts, chondrocytes, adipocytes and muscle cells. MSCs are also known to differentiate into neurons and glial cells in vitro, and in vivo following transplantation into the brain of animal models of neurological disorders including ischemia and intracerebral hemorrhage (ICH) stroke. In order to obtain sufficient number and homogeneous population of human MSCs, we have clonally isolated permanent and stable human MSC lines by transfecting primary cell cultures of fetal human bone marrow MSCs with a retroviral vector encoding v-myc gene. One of the cell lines, HM3.B10 (B10), was found to differentiate into neural cell types including neural stem cells, neurons, astrocytes and oligodendrocytes in vitro as shown by expression of genetic markers for neural stem cells (nestin and Musashi1), neurons (neurofilament protein, synapsin and MAP2), astrocytes (glial fibrillary acidic protein, GFAP) and oligodendrocytes (myelin basic protein, MBP) as determined by RT-PCR assay. In addition, B10 cells were found to differentiate into neural cell types as shown by immunocytochical demonstration of nestin (for neural stem cells), neurofilament protein and β-tubulin III (neurons) GFAP (astrocytes), and galactocerebroside (oligodendrocytes). Following brain transplantation in mouse ICH stroke model, B10 human MSCs integrate into host brain, survive, differentiate into neurons and astrocytes and induce behavioral improvement in the ICH animals. B10 human MSC cell line is not only a useful tool for the studies of organogenesis and specifically for the neurogenesis, but also provides a valuable source of cells for cell therapy studies in animal models of stroke and other neurological disorders

Effect of self-reported walking difficulty on bone mass and bone resorption marker in Japanese people aged 40?years and over

Background: This study aimed to examine the association of walking difficulty with bone mass or bone turnover among community-dwelling Japanese people aged 40 years and older. Methods: We studied 1097 community-dwelling Japanese people aged 40 years and older (379 men and 718 women) who were invited to participate in periodic health examinations in 2006?2009. Walking difficulty was defined as having difficulty walking 100 m on a level surface (self-administered questionnaire). Calcaneal stiffness index (bone mass) was measured by quantitative ultrasound. Spot urine samples were collected, and urinary N-terminal cross-linking telopeptide of type I collagen (NTx) was measured. Values were corrected for creatinine (Cre) concentration. Results: The prevalence of walking difficulty was significantly higher in women than in men (7.4 vs. 3.4 %, p?=?0.011) and significantly increased with age in men (p for trend?=?0.02) and women (p for trend <0.001). In univariate analysis, men and women with walking difficulty were older (p?<?0.001) and had a lower stiffness index (p?<?0.001), compared with those without walking difficulty. Among women, individuals with walking difficulty had significantly higher urinary NTx/Cre than those without walking difficulty (p?<?0.001); however, this was not so among men (p?=?0.39). Multiple regression analysis adjusted for age, weight, and menopausal status showed a significant association between walking difficulty and lower stiffness index in men (p?=?0.004) and women (p?=?0.005). In women, walking difficulty was significantly associated with higher NTx/Cre (p?=?0.001), but not in men (p?=?0.35). Conclusions: Walking difficulty may contribute to low bone mass in both sexes but might cause high bone turnover in women only

Zoledronic acid for treatment of Paget's disease of bone

Paget's disease of bone is characterised by a focal increase in bone resorption and bone formation. This anarchic metabolism leads to disorganised bone, with bone pain, fragility, deformity and compression of the peripheral or CNS according to the involved site. Quality of life of sufferers is dramatically impaired. Symptomatic therapy trends to relieve pain, but cannot seek to prevent other complications. Only 'specific' therapy can fulfil this purpose. Bisphosphonates have become the cornerstone for therapy of Paget's disease in the last 25 years. Progressively stronger bisphosphonates have been launched on the market. The last drug available, zoledronic acid, the most potent of this drug family, can be administered intravenously. It possesses a long-acting efficacy, allowing a follow up on a yearly basis and permitting the chance of a very long remission of the Pagetic lesion. In the long term, prevention of severe complications can be envisaged, with a reasonable pharmacoeconomic cost