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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Multinucleate osteoclasts originate from the fusion of macrophages, and play a major role in the resorption of bone. Osteoclasts are essential for bone development and remodelling, and increases in the number and/or activity of osteoclasts lead to diseases associated with generalized bone loss, such as osteoporosis, and others associated with localized bone loss, such as rheumatoid arthritis and periodontal disease. Because fusion is a key step in the differentiation of osteoclasts, a detailed understanding of the molecular mechanism of macrophage fusion should help develop strategies to prevent bone loss.

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Oteoblasts develop, synthesize, and deposit extracellular (osteoid) matrix comprising collagen and noncollagenous proteins, and participate in osteoid mineralization. The control of systemic inorganic phosphate (Pi) levels is known to be indispensable for bone formation, especially for osteoid mineralization processes, but the parathyroid hormone (PTH) (decreasing serum Pi levels)-vitamin D (increasing serum Pi levels) axis does not fully explain systemic Pi homeostasis. Attention has been paid to the role of local Pi handling by osteoblasts in bone mineralization. Two related sodium-Pi cotransporters, named Pit1 and Pit2, have been found in osteoblastic cell lines. Molecular inhibition of PiT1 abrogates differentiation and matrix mineralization in osteoblastic cells. In contrast, PiT1 overexpression in smooth muscle cells switches their phenotype from a contractile to an osteogenic one.
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Patients with X-linked hyper-IgM syndrome (XHIM), an inherited immune deficiency disorder caused by mutations in the gene encoding CD40 ligand (CD40L), have prominent osteopenia, leading to low-energy fractures, of unknown mechanism. This clinical observation prompted the investigators to ask whether CD40L deficiency may contribute to an imbalance in bone mineral homeostasis [1]. In this study, they show that, compared with age- and sex-matched normal controls, XHIM patients have significantly lower bone mineral density (BMD) and have elevated levels of N-terminal telopeptides of type I collagen (NTX), a urinary marker indicative of osteoclast activity.

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Bone repair is a key phenomenon to preserve skeleton stiffness and strength. It is not only important for fracture healing but also to repair bone microdamage resulting from mechanical constraints. The fist step in this regenerative procedure is the resorption of injured bone by efficient osteoclasts, followed by synthesis of new bone by osteoblasts.

Bone morphogenetic protein 2 (BMP2), synthesized by osteoblasts, accumulates in the extracellular matrix and was acknowledged as a factor promoting fracture repair in adult bone [1]. In order to evaluate the role of BMP2 during growth, Tsuji et al. [2] generated transgenic mice in which Bmp2 was inactivated in a limb-specific manner before the onset of skeletal development. These mice have few skeletal abnormalities at birth, suggesting that other BMPs present in the developing limb can compensate, at that stage, for the loss of BMP2.

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Various molecules coordinate osteoclast function with that of osteoblasts, such as the RANK/RANKL pathway. However, molecules that mediate osteoclast-osteoblast interactions by simultaneous signal transduction in both cell types have not yet been identified.

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Matrix-producing osteoblasts and bone-resorbing osteoclasts maintain bone homeostasis. Osteoclasts are multinucleated, giant cells of hematopoietic origin formed by the fusion of mononuclear preosteoclasts derived from myeloid cells. Fusion-mediated giant cell formation is critical for osteoclast maturation; without it, bone resorption is inefficient. One gene predominantly expressed in osteoclasts is the d2 isoform of vacuolar (H+) ATPase (v-ATPase) V0 domain (Atp6v0d2). What is the function of this protein?

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Bone morphogenetic proteins (BMPs) are members of the TGFβ superfamily synthesized by bone cells and playing a major role in differentiation of the bone cell lineages. One of these proteins, BMP2, is synthesized by osteoblasts and accumulates in the extracellular matrix. It exerts paracrine effects at the vicinity of its sites of synthesis and its importance in bone development and repair has been acknowledged [1, 2].

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