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Query: UNIPROT:P06889 (Mol)
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Alternative mechanisms of steroid action, through both traditional nuclear receptors and indirect pathways of gene activation, are emerging. Recent studies suggest that the synthetic steroid, 4-estrene-3alpha,17beta-diol (estren), has nongenotropic as well as sex-nonspecific osteogenic effects in ovariectomized and orchidectomized mice. We found limited estrogen receptor-dependent effects by estren on gene expression in primary osteoblast cultures and showed that it binds poorly to estrogen and androgen receptors in vitro. However, estren potently regulated direct and indirect androgen receptor-dependent effects on gene expression by osteoblasts. Consistent with this, osteoblasts produced the potent androgen 19-nortestosterone from estren by way of a 3alpha-hydroxysteroid dehydrogenase-like activity. Moreover, recombinant 3alpha-hydroxysteroid dehydrogenase (AKR1C9) and osteoblast-derived cell lysate each effectively converted estren to 19-nortestosterone in vitro, and mRNA encoding this enzyme occurs in osteoblasts. In addition to its androgenic activity, estren potently stimulated androgen receptor-dependent effects on gene expression through conventional estrogen-sensitive transcriptional elements in osteoblasts. Therefore, through local metabolism, estren indirectly activates the androgen receptor to regulate both androgen- and estrogen-like transcriptional responses by bone-forming cells.
Mol Endocrinol 2004 May
PMID:Estren (4-estren-3alpha,17beta-diol) is a prohormone that regulates both androgenic and estrogenic transcriptional effects through the androgen receptor. 1476 54

Viral delivery of the therapeutic gene bone morphogenetic protein-2 (BMP-2) is a promising approach for bone regeneration. The human parvovirus adeno-associated virus (AAV) type 2 is considered one of the most encouraging viral vector systems because of its high transduction rates and biosafety ratings. Bone morphogenetic protein-2 is a highly potent osteoinductive protein, which induces bone formation in vivo and osteogenic differentiation in vitro. The exogenous regulation of BMP-2 expression in bone-regenerating sites is required to control BMP-2 protein secretion, thus promoting safe and controlled bone formation and regeneration. We have therefore constructed a dual-construct vector for the recombinant AAV (rAAV)-based recombinant human BMP-2 (rhBMP-2) gene delivery system, which is regulated by the tetracycline-sensitive promoter (TetON). Each vector was encapsidated separately, yielding two recombinant viruses. We evaluated the efficiency of rAAV-hBMP-2 to induce bone formation in ectopic and orthotopic sites. Doxycycline (Dox), an analogue of tetracycline, was orally administered to mice via their drinking water to induce rhBMP-2 expression. Bone formation was measured using quantitative imaging-microcomputerized tomography and cooled charge-coupled device imaging-to detect osteogenic activity at the cellular level, detecting osteocalcin expression. The rAAV-hBMP-2-treated mice that were given Dox demonstrated bone formation in both in vivo models compared to none in mice prevented from receiving Dox. Thus, the Tet-regulated rAAV-hBMP-2 vector is an effective means of induction and regulation of bone regeneration and repair.
Mol Ther 2004 Apr
PMID:Gene therapy platform for bone regeneration using an exogenously regulated, AAV-2-based gene expression system. 1509 89

Bone regenerates following amputation through the level of the nail, but bone is capped following amputation through more proximal levels. Because osteogenesis requires an ample blood supply, we postulated that a restricted vascular supply might be correlated with restricted regenerative ability at proximal levels. More than 40 rats and mice were injected with ink or resin to visualize vascular supplies of intact, regenerating, and nonregenerating rat and mouse digits. Ink-injected specimens were viewed as histological sections or cleared whole mounts. Partially digested resin casts were viewed using scanning electron microscopy. Contrary to our hypothesis, prior to amputation, proximal sites are more vascular than distal sites. At both proximal and distal levels, endosteal and periosteal vascular systems are evident. However, in proximal phalanges, additional subcutaneous and dermal layers encircle the bone. Beneath the distal nail, these layers are absent, and a single layer of vessels provides both periosteal and cutaneous supplies. After amputation at both levels, new vessels sprout profusely in osteogenic areas of both endosteum and periosteum. However, at proximal levels, the additional hypodermal and dermal vessels contribute to a vascular plexus that, paradoxically, may impair bone regrowth by contributing to the formation of dermal scar rather than bone.
Anat Rec A Discov Mol Cell Evol Biol 2004 May
PMID:Vascular supplies differ in regenerating and nonregenerating amputated rodent digits. 1510 39

The present ultrastructural investigation into osteocyte dendrogenesis represents a continuation of a previous study (Ferretti et al., Anat. Embryol., 2002; 206:21-29), in which we pointed out that, during intramembranous ossification, the well-known dynamic bone formation (DBF), performed by migrating osteoblast laminae, is preceded by static bone formation (SBF), in which cords of stationary osteoblasts transform into osteocytes in the same site where they differentiated. The research was carried out on the perichondral center of ossification surrounding the mid shaft level of various long bones of chick embryos and newborn rabbits. Transmission electron microscope observations showed that the formation of osteocyte dendrites is quite different in the two types of osteogenesis, mainly depending on whether or not osteoblast movement occurs. In DBF, osteoblasts transform into small ovoidal/ellipsoidal osteocytes and their dendrites form in an asynchronous and asymmetrical manner in concomitance with, and depending on, the advancing mineralizing surface and the receding osteogenic laminae. In SBF, stationary osteoblasts give rise to big globous osteocytes, located inside confluent lacunae, with short and symmetrical dendrites that can radiate simultaneously all around their cell body because they are completely surrounded by unmineralized matrix. Contacts and gap junctions were observed between all osteocytes (both SBF- and DBF-derived) and between osteocytes and osteoblasts. Finally, a continuous osteocyte network extends throughout the bone, regardless of its static or dynamic origin. This network has the characteristic of a functional syncytium, potentially capable of modulating, by wiring transmission, the cells of the osteogenic lineage covering the bone surfaces.
Anat Rec A Discov Mol Cell Evol Biol 2004 May
PMID:Osteocyte dendrogenesis in static and dynamic bone formation: an ultrastructural study. 1510 43

Bone morphogenetic and osteogenic proteins (BMPs/OPs), members of the transforming growth factor-beta (TGF-beta) superfamily, are soluble mediators of tissue morphogenesis and induce de novo endochondral bone formation in heterotopic extraskeletal sites as a recapitulation of embryonic development. In the primate Papio ursinus, the induction of bone formation has been extended to the TGF-beta isoforms per se. In the primate and in the primate only, the TGF-beta isoforms are initiators of endochondral bone formation by induction and act in a species-, site- and tissue-specific mode with robust endochondral bone induction in heterotopic sites but with limited new bone formation in orthotopic bone defects. The limited inductive capacity orthotopically of TGF-beta isoforms is associated with expression of the inhibitory Smads, Smad6 and Smad7. In primates, bone formation can also be induced using biomimetic crystalline hydroxyapatite matrices with a specific surface geometry and without the exogenous application of osteogenic proteins of the TGF-beta superfamily, even when the biomimetic matrices are implanted heterotopically in the rectus abdominis muscle. The sequence of events that directs new bone formation upon the implantation of highly crystalline biomimetic matrices initiates with vascular invasion, mesenchymal cell migration, attachment and differentiation of osteoblast-like cells attached to the substratum, expression and synthesis of osteogenic proteins of the TGF-beta superfamily resulting in the induction of bone as a secondary response. The above findings in the primate indicate enormous potential for the bioengineering industry. Of particular interest is that biomimetic matrices with intrinsic osteoinductivity would be an affordable option in the local context.
J Cell Mol Med
PMID:Soluble, insoluble and geometric signals sculpt the architecture of mineralized tissues. 1525 65

It is well documented that adult cartilage has minimal self-repair ability. Current methods for treatment of cartilage injury focus on the relief of pain and inflammation and have met with limited long-term success. In the forefront of new therapeutic approaches, autologous chondrocyte transplantation is still only applied to a very small percentage of the patient population. Our laboratory has focused on cartilage repair using progenitor cells and studied their differentiation into cartilage. Adult mesenchymal stem cells are an attractive candidate as progenitor cells for cartilage repair because of their documented osteogenic and chondrogenic potential, ease of harvest, and ease of expansion in culture; furthermore, their use will obviate the need for harvesting precious healthy cartilage from a patient to obtain autologous chondrocytes for transplantation. However, the need to induce chondrogenic differentiation in the mesenchymal stem cells is superposed on other technical issues associated with cartilage repair; this adds a level of complexity over using mature chondrocytes. This chapter focuses on the methods involved in the isolation of human mesenchymal stem cells and their differentiation along the chondrogenic lineage. Although we have the technology to accomplish chondrogenic differentiation of stem cells, much is still to be learned regarding the regulatory mechanisms controlling the lineage transitions and maturation of the cartilaginous tissue.
Methods Mol Med 2004
PMID:Generation of pluripotent stem cells and their differentiation to the chondrocytic phenotype. 1528 May 87

Genetic studies show that Msx2 and Dlx5 homeodomain (HD) proteins support skeletal development, but null mutation of the closely related Dlx3 gene results in early embryonic lethality. Here we find that expression of Dlx3 in the mouse embryo is associated with new bone formation and regulation of osteoblast differentiation. Dlx3 is expressed in osteoblasts, and overexpression of Dlx3 in osteoprogenitor cells promotes, while specific knock-down of Dlx3 by RNA interference inhibits, induction of osteogenic markers. We characterized gene regulation by Dlx3 in relation to that of Msx2 and Dlx5 during osteoblast differentiation. Chromatin immunoprecipitation assays revealed a molecular switch in HD protein association with the bone-specific osteocalcin (OC) gene. The transcriptionally repressed OC gene was occupied by Msx2 in proliferating osteoblasts, while Dlx3, Dlx5, and Runx2 were recruited postproliferatively to initiate transcription. Dlx5 occupancy increased over Dlx3 in mature osteoblasts at the mineralization stage of differentiation, coincident with increased RNA polymerase II occupancy. Dlx3 protein-DNA interactions stimulated OC promoter activity, while Dlx3-Runx2 protein-protein interaction reduced Runx2-mediated transcription. Deletion analysis showed that the Dlx3 interacting domain of Runx2 is from amino acids 376 to 432, which also include the transcriptionally active subnuclear targeting sequence (376 to 432). Thus, we provide cellular and molecular evidence for Dlx3 in regulating osteoprogenitor cell differentiation and for both positive and negative regulation of gene transcription. We propose that multiple HD proteins in osteoblasts constitute a regulatory network that mediates development of the bone phenotype through the sequential association of distinct HD proteins with promoter regulatory elements.
Mol Cell Biol 2004 Oct
PMID:Dlx3 transcriptional regulation of osteoblast differentiation: temporal recruitment of Msx2, Dlx3, and Dlx5 homeodomain proteins to chromatin of the osteocalcin gene. 1545 94

The laminin family of proteins is critical for managing a variety of cellular activities including migration, adhesion, and differentiation. In bone, the roles of laminins in controlling osteogenic differentiation of human mesenchymal stem cells (hMSC) are unknown. We report here that laminin-5 is found in bone and expressed by hMSC. hMSC isolated from bone synthesize laminin-5 and adhere to exogenous laminin-5 through alpha3beta1 integrin. Adhesion to laminin-5 activates extracellular signal-related kinase (ERK) within 30 min and leads to phosphorylation of the osteogenic transcription factor Runx2/CBFA-1 within 8 d. Cells plated on laminin-5 for 16 d express increased levels of osteogenic marker genes, and those plated for 21 d deposit a mineralized matrix, indicative of osteogenic differentiation. Addition of the ERK inhibitor PD98059 mitigates these effects. We conclude that contact with laminin-5 is sufficient to activate ERK and to stimulate osteogenic differentiation in hMSC.
Mol Biol Cell 2005 Feb
PMID:Laminin-5 induces osteogenic gene expression in human mesenchymal stem cells through an ERK-dependent pathway. 1557 77

Bone morphogenetic proteins (BMPs) are multi-functional growth factors that belong to the transforming growth factor beta (TGFbeta) superfamily. The roles of BMPs in embryonic development and cellular functions in postnatal and adult animals have been extensively studied in recent years. Signal transduction studies have revealed that Smad1, 5 and 8 are the immediate downstream molecules of BMP receptors and play a central role in BMP signal transduction. Studies from transgenic and knockout mice and from animals and humans with naturally occurring mutations in BMPs and related genes have shown that BMP signaling plays critical roles in heart, neural and cartilage development. BMPs also play an important role in postnatal bone formation. BMP activities are regulated at different molecular levels. Preclinical and clinical studies have shown that BMP-2 can be utilized in various therapeutic interventions such as bone defects, non-union fractures, spinal fusion, osteoporosis and root canal surgery. Tissue-specific knockout of a specific BMP ligand, a subtype of BMP receptors or a specific signaling molecule is required to further determine the specific role of a BMP ligand, receptor or signaling molecule in a particular tissue. BMPs are members of the TGFbeta superfamily. The activity of BMPs was first identified in the 1960s (Urist, M.R. (1965) "Bone formation by autoinduction", Science 150, 893-899), but the proteins responsible for bone induction remained unknown until the purification and sequence of bovine BMP-3 (osteogenin) and cloning of human BMP-2 and 4 in the late 1980s (Wozney, J.M. et al. (1988) "Novel regulators of bone formation: molecular clones and activities", Science 242, 1528-1534; Luyten, F.P. et al. (1989) "Purification and partial amino acid sequence of osteogenin, a protein initiating bone differentiation", J. Biol. Chem. 264, 13377-13380; Wozney, J.M. (1992) "The bone morphogenetic protein family and osteogenesis", Mol. Reprod. Dev. 32, 160-167). To date, around 20 BMP family members have been identified and characterized. BMPs signal through serine/threonine kinase receptors, composed of type I and II subtypes. Three type I receptors have been shown to bind BMP ligands, type IA and IB BMP receptors (BMPR-IA or ALK-3 and BMPR-IB or ALK-6) and type IA activin receptor (ActR-IA or ALK-2) (Koenig, B.B. et al. (1994) "Characterization and cloning of a receptor for BMP-2 and BMP-4 from NIH 3T3 cells", Mol. Cell. Biol. 14, 5961-5974; ten Dijke, P. et al. (1994) "Identification of type I receptors for osteogenic protein-1 and bone morphogenetic protein-4", J. Biol. Chem. 269, 16985-16988; Macias-Silva, M. et al. (1998) "Specific activation of Smad1 signaling pathways by the BMP7 type I receptor, ALK2", J. Biol. Chem. 273, 25628-25636). Three type II receptors for BMPs have also been identified and they are type II BMP receptor (BMPR-II) and type II and IIB activin receptors (ActR-II and ActR-IIB) (Yamashita, H. et al. (1995) "Osteogenic protein-1 binds to activin type II receptors and induces certain activin-like effects", J. Cell. Biol. 130, 217-226; Rosenzweig, B.L. et al. (1995) "Cloning and characterization of a human type II receptor for bone morphogenetic proteins", Proc. Natl Acad. Sci. USA 92, 7632-7636; Kawabata, M. et al. (1995) "Cloning of a novel type II serine/threonine kinase receptor through interaction with the type I transforming growth factor-beta receptor", J. Biol. Chem. 270, 5625-5630). Whereas BMPR-IA, IB and II are specific to BMPs, ActR-IA, II and IIB are also signaling receptors for activins. These receptors are expressed differentially in various tissues. Type I and II BMP receptors are both indispensable for signal transduction. After ligand binding they form a heterotetrameric-activated receptor complex consisting of two pairs of a type I and II receptor complex (Moustakas, A. and C.H. Heldi (2002) "From mono- to oligo-Smads: the heart of the matter in TGFbeta signal transduction" Genes Dev. 16, 67-871). The type I BMP receptor substrates include a protein family, the Smad proteins, that play a central role in relaying the BMP signal from the receptor to target genes in the nucleus. Smad1, 5 and 8 are phosphorylated by BMP receptors in a ligand-dependent manner (Hoodless, P.A. et al. (1996) "MADR1, a MAD-related protein that functions in BMP2 signaling pathways", Cell 85, 489-500; Chen Y. et al. (1997) "Smad8 mediates the signaling of the receptor serine kinase", Proc. Natl Acad. Sci. USA 94, 12938-12943; Nishimura R. et al. (1998) "Smad5 and DPC4 are key molecules in mediating BMP-2-induced osteoblastic differentiation of the pluripotent mesenchymal precursor cell line C2C12", J. Biol. Chem. 273, 1872-1879). After release from the receptor, the phosphorylated Smad proteins associate with the related protein Smad4, which acts as a shared partner. This complex translocates into the nucleus and participates in gene transcription with other transcription factors (). A significant advancement about the understanding of in vivo functions of BMP ligands, receptors and signaling molecules has been achieved in recent years.
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PMID:Bone morphogenetic proteins. 1562 26

We previously reported that PP1gamma1 is highly expressed in osteosarcoma and chondrosarcoma, and suggested that this protein plays a role in malignancy of osteogenic tumors. In this study, we investigated the correlation of the expression of PP1gamma1 with telomerase activity. PP2A protein was not positive in any of the 5 cases of Ewing's sarcoma, but PP1gamma1 protein was strongly positive in all cases. Furthermore, malignant cells had high telomerase activity. We investigated the correlation of the expression of PP1gamma1 with telomerase activity, and showed that telomerase activity is regulated by protein phosphorylation in Ewing's sarcoma cells.
Res Commun Mol Pathol Pharmacol 2003
PMID:Enhanced expression of PP1gamma1, a catalytic subunit isoform of protein phosphatase type1 and expression of telomerase activity in Ewing's sarcoma cells. 1568 25


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