Tissue engineering of large bone defects is approached through implantation of autologous osteogenic cells, named multipotent stromal cells or mesenchymal stem cells (MSCs). The ability of human MSCs to differentiate into adipogenic, chondrogenic, osteogenic, and myogenic lineages has generated a great deal of potential clinical use in regenerative medicine and tissue engineering in the past decade. Although animal-derived MSCs successfully bridge large bone defects, models for ectopic bone formation as well as recent clinical trials demonstrate that bone formation by human MSCs is inadequate. Predifferentiation of human MSCs into the osteogenic lineage in vitro during the expansion phase before implantation offers an opportunity to improve their in vivo performance.

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Osteoclasts are cells of a hematopoetic lineage that resorb bone, and excessive activity of these cells can lead to low bone mass with an associated increased incidence of fractures. Osteoclast differentiation requires the transcription factor AP-1, which is a heterodimer of a Jun family member and a Fos family member.

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RANK ligand (RANKL) is produced by osteoblasts and is an essential mediator for osteoclast development. No study has examined in detail the direct skeletal consequences of excess RANKL on bone turnover, mineralization, architecture, and vascular calcification. The authors of a recent study [1] administered soluble RANKL continuously to mature rats and created a bone-loss model. Six-month-old Sprague-Dawley rats were assigned to three groups (n=12) receiving continuous administration of saline (VEH) or human RANKL (35 μg/kg/day or 175 μg/kg/day) for 28 days. Blood was collected routinely during the study. At sacrifice, hind limbs and aorta were removed and samples were analyzed.

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Animal studies provided evidence that osteoclast-derived ephrinB2 can act through its receptor, EphB4, in osteoblasts to promote osteoblast differentiation and that reverse signaling by osteoblast-derived EphB4 can suppress the formation of osteoclast precursors in a contact-dependent process. With the aim of identifying new pathways and genes regulated by PTH and PTH-related protein (PTHrP) in osteoblasts, this study [2] was carried out using a mouse marrow stromal cell line, Kusa 4b10, that acquires features of the osteoblastic phenotype in long-term culture conditions. After the appearance of functional PTH receptor 1 (PTHR1) in Kusa 4b10 cells, they were treated with either PTH or PTHrP, and RNA was subjected to whole mouse genome array. The microarray data were validated using quantitative real-time RT-PCR on independently prepared RNA samples from differentiated Kusa 4b10, UMR106 osteosarcoma cells, and primary mouse calvarial osteoblasts, as well as in vivo using RNA from metaphyseal bone after a single PTH injection.

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Major depressive disorder is a common condition and a major cause of disability. Besides mood changes, depression is associated with increased morbidity and non–suicide-related mortality. In addition to poor medical compliance and lifestyle factors, endocrine, immune, and autonomic dysregulation may play a causative role in producing medical illnesses in patients with major depression. An increased prevalence of low bone mineral density (BMD) has been reported in patients with major depressive disorder, mostly women. Moreover, antidepressants such as selective serotonin reuptake inhibitors (SSRIs) may affect bone density and fracture risk per se, depending on the age of patients. The association of major depression disorder and BMD was investigated in a prospective study of bone turnover in which immune, pituitary-adrenal, and sympathetic biomarkers were measured [1]. The authors sought to determine whether premenopausal women with major depression had a higher prevalence of osteopenia and osteoporosis and of lower BMD than did healthy women. Baseline BMD was measured in 89 premenopausal women with major depression and 44 healthy control women enrolled in a prospective study of bone turnover. The BMD was measured by dual energy x-ray absorptiometry at the spine, hip, and forearm. Mean hourly levels of plasma 24-hour cytokines, 24-hour urinary free cortisol, and catecholamine excretion were measured in a subset of women.

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