An imbalance in bone formation relative to bone resorption results in the net bone loss that occurs in osteoporosis and inflammatory bone diseases. Although it is well known that RANKL/RANK stimulate bone resorption by activating nuclear factor-kB (NF-kB) in osteoclasts, the molecular mechanisms that mediate impaired bone formation are poorly understood.

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The recent identification of the genes responsible for several human genetic diseases affecting bone homeostasis and the characterization of mouse models for these diseases indicated that canonical Wnt signaling plays a critical role in the control of bone mass [1]. A recent study [2] reports that the osteoblast-specific transcription factor Osterix (Osx), which is required for osteoblast differentiation, inhibits Wnt pathway activity. In calvarial cells of Osx-null embryos, expression of the Wnt antagonist Dkk1 was abolished, and that of Wnt target genes c-Myc and cyclin D1 was increased. Moreover, these studies demonstrated that Osx bound to and activated the Dkk1 promoter. In addition, Osx inhibited β-catenin-induced reporter activity and β-catenin-induced secondary axis formation in Xenopus embryos. Importantly, data from calvaria of Osx-null embryos indicate that Osx inhibited the Wnt pathway in osteoblasts in vivo. This study further shows that Osx disrupts binding of transcription factor TCF to DNA. This provides a likely mechanism for the inhibition by Osx of β-catenin transcriptional activity.
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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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Mesenchymal stem/progenitor cells (MSCs) can differentiate into adipocytes, muscle cells, osteoblasts, or cartilage and possess potential for tissue repair in patients with osteoporosis, diseased joints, and myocardial infarction. Many groups have investigated strategies involving the infusion of MSCs for the purpose of regenerative therapy; however, problems concerning MSC homing to diseased sites and the use of allogeneic MSCs have limited this approach. Therefore, the ability to use pharmacological agents to induce the differentiation of resident MSCs toward a certain lineage in vivo is an important therapeutic goal. In a recent study [1], the authors report that bortezomib, a clinically available proteasome inhibitor active against myeloma, induces the differentiation of MSCs into osteoblasts, resulting in new bone formation.

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Bone adjusts its structure to become better suited to withstand the mechanical demands it experiences. Physical loading and routine activities have been shown to inhibit bone resorption. However, the cellular mechanism underlying this phenomenon remains largely unknown. The focus of a recent study [1] was to determine the mechanisms by which osteocytes might transduce and regulate bone resorption, and the antiresorptive effects of loading.
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Calcineurin is a protein phosphatase that regulates several physiological processes and is the target for cyclosporine A. Pharmacological inhibition of calcineurin by low concentrations of cyclosporin A increases osteoblast differentiation in vitro and bone mass in vivo. To determine whether calcineurin exerts direct actions on osteoblasts, the authors of a recent study [1] generated mice lacking a calcineurin regulatory subunit selectively in osteoblasts.
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The differentiation of multipotent stemcells of mesodermal origin results in the formation of adipocytes, chondrocytes, osteoblasts, and myoblasts. In humans, osteoporosis and age-related osteopenia are associated with an increase in marrow fat tissue and osteoblast numbers correlated negatively with the number of adipocytes. Osteoblastic differentiation is driven by runx2, and then characterized by the expression of alkaline phosphatase, osteocalcin, and eventually by the mineralization of the extracellular matrix.
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