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Search Results to Jane B Lian PhD

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Academic Background

Associate Professor of Biological Chemistry, Harvard Medical School, Boston

Senior Research Associate, Department of Orthopaedic Surgery, Children's Hospital Medical Center, Boston

Post-doctoral training: National Institutes of Health; Harvard Medical School, Children's Hospital.

Ph.D., Boston University School of Medicine

Molecular Mechanisms Regulating Skeletal Development and Metastasis of Cancer Cells to Bone

Bone tissue functions as a mechanically responsive structural component of the body and as a major organ essential for maintaining calcium and phosphate homeostasis. The skeleton is the target of numerous human genetic disorders and recently mouse models have identified new regulatory pathways that affect the skeleton. As a normal process of aging and hormonal changes after the menopause, skeletal mass can decrease by as much as 30% leading to bone fracture and compromised quality of life in the elderly population. Historically the laboratory has addressed molecular mechanisms regulating formation and mineralization of bone by osteoblasts and turnover of bone tissue by osteoclasts, the bone resorbing cells. We are defining the key regulatory events for the progressive differentiation of osteoprogenitor stem cells to osteogenic cells by identifying transcription factor complexes that control expression of tissue-specific genes. Our studies are showing that early events of skeletal development are recapitulated in the adult skeleton for the normal maintenance of bone mass.

The skeleton is also a target of metastatic cancers and recent studies from our laboratory and others are demonstrating that signaling pathways which mediate responsiveness of the bone forming and bone resorbing cells of the skeleton for organogenesis are also pathways that are activated in cancer cells which metastasize to bone.

Areas of current investigation for graduate and MD/PhD students and postdoctoral fellows include:

1.   Combinatorial Control Mechanisms for Skeletal Development

This laboratory is defining a regulatory network of developmental factors with a focus on three major pathways critical for skeletal pattern formation, early embryonic bone development, and osteoblast differentiation:  the bone morphogenetic protein (BMP) family, the Wnt signaling pathway and Hox homeodomain factors.  The integration of these signaling pathways for tissue-specific gene expression is being characterized for two genes, the transcription factor Runx2/Cbfa1 established as essential for skeletal development and a bone-specific Runx2 target gene, osteocalcin, that represents one of the major non-collagenous bone matrix proteins (Choi et al., 2001; Lengner et al., 2002).  The Runx2/Cbfa transcription factor is essential for osteogenic differentiation and functions as a master regulatory gene through multiple properties (Fig. 1). Runx2 can change the phenotype of a cell, e.g., from a non-osseous adipocyte to an osteoblast, as well as control recruitment of stem cells into the chondrogenic and osteogenic phenotype (Lengner et al., 2005).  Characterizing the functional activities of this protein has provided new paradigms for understanding gene regulation.  First, Runx2 expression is regulated in stem cells by early development cues including Hox genes, BMP/TGFb, and Wnt proteins (Balint et al., 2003, Zaidi et al., 2002; Gaur et al., 2005, 2006; Bodine et al., 2004).  Secondly, this transcription factor is a scaffolding protein that is targeted to specific subnuclear domains for the assembly of multimeric complexes on target genes (reviewed in Lian et al., 2004).  Third, Runx2 recruits chromatin remodeling proteins and assembles complexes at Runx2 regulatory elements in genes to either activate or repress gene transcription (Javed et al., 1999; Young et al., 2005).  By mutational analyses of different protein interacting domains of Runx2, we are identifying the coregulatory proteins essential for osteoblast differentiation in vitro and for skeletal development in vivo (Zaidi et al., 2004; Afzal et al., 2005). Experimental approaches include cell culture models for chondrocyte and osteoblast differentiation using human embryonic and mesenchymal stem cells, gene regulation studies and characterization of mouse phenotypes. 

2.  Tissue Specific Gene Regulatory Mechanisms

The osteocalcin gene encodes a calcium binding ECM protein that is developmentally regulated during bone formation by a plethora of hormones, growth factors, and cell signaling proteins involved in calcium homeostasis and bone remodeling. The integration of independent signals must converge on the promoter to account for complex physiologic control of the gene during bone formation and turnover. Thus, the promoter of the osteocalcin gene provides a molecular blueprint for understanding developmental and hormonal regulation of gene expression required for bone formation (Hassan et al., 2004; Javed et al., 1999; Gutierrez et al., 2004). Identification of tissue-specific regulatory sequences and their cognate binding factors have allowed us to develop strategies for cell based therapy to target therapeutic genes specifically to bone. Examples of osteocalcin tissue-specific regulatory elements undergoing characterization include the steroid response elements, runt homology (Runx/Cbfa), homeodomain (HD), Hox, C/EBP, ATF and AP-1 protein binding sites.  The HD proteins (Msx, Dlx) and Hoxa10 regulate osteocalcin at different stages of cell differentiation (Fig. 2). Transcriptional control of the gene is evaluated at multiple levels including chromatin modifications and recruitment of transcription factors and their coregulatory proteins by chromatin immunoprecipitation studies.  Enforced expression and siRNA knockdown studies of regulatory factors strategies are used to establish their function in vitro and in vivo using transgenic mouse models. Such analyses have revealed new insights into understanding the complex interplay of physiologic mediators of tissue differentiation. This program of research provides a student with fundamental techniques requisite for characterizing gene regulation and expression in a biological context.

3.  Cancer Cell Biology in the Bone Microenvironment

The end stage of breast and prostate cancer is metastasis to bone, with very poor prognosis with nearly 70% mortality within a year.  Cancer cells cause destruction of the bone, resulting in fractures and severe pain.  Understanding the mechanisms which induce metastasis of the primary cancer cell to the bone environment needs to be addressed.  We have identified high expression levels of the Runx2 transcription factor in metastatic breast and prostate cancer cell lines.  Runx target genes in the cancer cell include the entire class of matrix metalloproteinases characterized for their role in tissue invasion, the vascular endothelial growth factor, a potent angiogenic factor involved as a primary event in tumor growth and several cell growth and osteoblastic genes expressed in the bone environment that allow for tumor growth (Fig. 3) (Pratap et al., 2005).  The cancer cell responds to TGFb and BMP growth factors in the bone extracellular matrix and stimulates bone resorbing cells.  In recent studies, we have shown metastatic cancer cell lines in which Runx2 activity has been blocked through genetic mutations, that the osteolytic disease of breast cancer cells can be prevented in the mouse (Barnes et al., 2004; Javed et al., 2005). The presence of mutant Runx2 protein in metastatic cells inhibits cell invasion (in vitro assays) and genes associated with tumor growth (Fig. 3).  We are now turning our attention to mechanisms responsible for activation of Runx2 in the primary tumor that would lead to the metastatic event in vivo.  Experimental approaches include generation of human cancer cell lines with mutants of Runx2, assessing tumor growth by in vivo imaging of tumors in breast, prostate and bone tissues, and examining gene expression profiles of the tumors are assayed.

4.  Gene Therapy and Tissue Engineering for Skeletal Diseases

Genetic disorders of the skeleton require expression of the normal proteins, specifically in bone cells.   Here the osteocalcin gene promoter provides the appropriate method for targeting expressed genes to mature osteoblasts.  Using OC-EGFP mice, we are characterizing a population of mesenchymal stem cells from these mice that differentiate into bone cells expressing GFP in donor mice.  Numerous donor mice carrying mutated genes that mimic human genetic disorders are available for addressing the critical number of mesenchymal stem cells differentiated to osteoblasts that can provide a sufficient level of normal protein to correct the skeletal disorder.  A second example where tissue engineering is being developed relates to the problem of non-union fractures where scar tissue rather than new bone formation occurs.  By using autologous cells expressing osteogenic factors, bone formation can be induced.  Lastly, we are culturing human embryonic stem cells and promoting their differentiation to chondrogenic and osteogenic lineages and testing these in mouse models.  These powerful properties are being exploited for treatment of skeletal diseases that require rebuilding of skeletal tissue by promoting lineage allocation of stem cells or marrow progenitor cells. 

Figures

 Figure 1

 

  Lian Figure 1

 Figure 2

 

  Lian Figure 2
  

 Figure 3

 

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One or more keywords matched the following items that are connected to Lian, Jane

Item TypeName
Academic Article CCAAT/enhancer-binding proteins (C/EBP) beta and delta activate osteocalcin gene transcription and synergize with Runx2 at the C/EBP element to regulate bone-specific expression.
Academic Article Integration of Runx and Smad regulatory signals at transcriptionally active subnuclear sites.
Academic Article Identification of novel protein/DNA interactions within the promoter of the bone-related transcription factor Runx2/Cbfa1.
Academic Article Activation of the bone-related Runx2/Cbfa1 promoter in mesenchymal condensations and developing chondrocytes of the axial skeleton.
Academic Article Intranuclear trafficking of transcription factors: Requirements for vitamin D-mediated biological control of gene expression.
Academic Article Phenotype discovery by gene expression profiling: mapping of biological processes linked to BMP-2-mediated osteoblast differentiation.
Academic Article Intranuclear organization of RUNX transcriptional regulatory machinery in biological control of skeletogenesis and cancer.
Academic Article Runx2 control of organization, assembly and activity of the regulatory machinery for skeletal gene expression.
Academic Article Primary mouse embryonic fibroblasts: a model of mesenchymal cartilage formation.
Academic Article Overlapping expression of Runx1(Cbfa2) and Runx2(Cbfa1) transcription factors supports cooperative induction of skeletal development.
Academic Article Smad function and intranuclear targeting share a Runx2 motif required for osteogenic lineage induction and BMP2 responsive transcription.
Academic Article Impaired intranuclear trafficking of Runx2 (AML3/CBFA1) transcription factors in breast cancer cells inhibits osteolysis in vivo.
Academic Article Secreted frizzled related protein 1 regulates Wnt signaling for BMP2 induced chondrocyte differentiation.
Academic Article Networks and hubs for the transcriptional control of osteoblastogenesis.
Academic Article HOXA10 controls osteoblastogenesis by directly activating bone regulatory and phenotypic genes.
Academic Article Cooperation between p27 and p107 during endochondral ossification suggests a genetic pathway controlled by p27 and p130.
Academic Article Structural coupling of Smad and Runx2 for execution of the BMP2 osteogenic signal.
Academic Article Vitamin D control of gene expression: temporal and spatial parameters for organization of the regulatory machinery.
Academic Article Chromatin immunoprecipitation assays: application of ChIP-on-chip for defining dynamic transcriptional mechanisms in bone cells.
Academic Article Expression of secreted frizzled related protein 1, a Wnt antagonist, in brain, kidney, and skeleton is dispensable for normal embryonic development.
Academic Article Elastomeric high-mineral content hydrogel-hydroxyapatite composites for orthopedic applications.
Academic Article Intricate gene regulatory networks of helix-loop-helix (HLH) proteins support regulation of bone-tissue related genes during osteoblast differentiation.
Academic Article New insights in bone biology: unmasking skeletal effects of the extracellular calcium-sensing receptor.
Academic Article A microRNA signature for a BMP2-induced osteoblast lineage commitment program.
Academic Article Runx2 transcriptional activation of Indian Hedgehog and a downstream bone metastatic pathway in breast cancer cells.
Academic Article Co-stimulation of the bone-related Runx2 P1 promoter in mesenchymal cells by SP1 and ETS transcription factors at polymorphic purine-rich DNA sequences (Y-repeats).
Academic Article A Runx2 threshold for the cleidocranial dysplasia phenotype.
Academic Article Secreted frizzled related protein 1 is a target to improve fracture healing.
Academic Article The gene for aromatase, a rate-limiting enzyme for local estrogen biosynthesis, is a downstream target gene of Runx2 in skeletal tissues.
Academic Article Frequent attenuation of the WWOX tumor suppressor in osteosarcoma is associated with increased tumorigenicity and aberrant RUNX2 expression.
Academic Article Reduced CpG methylation is associated with transcriptional activation of the bone-specific rat osteocalcin gene in osteoblasts.
Academic Article Histone acetylation in vivo at the osteocalcin locus is functionally linked to vitamin D-dependent, bone tissue-specific transcription.
Academic Article 1,25-(OH)2-vitamin D3 suppresses the bone-related Runx2/Cbfa1 gene promoter.
Academic Article Cancer-related ectopic expression of the bone-related transcription factor RUNX2 in non-osseous metastatic tumor cells is linked to cell proliferation and motility.
Academic Article Effects of miR-335-5p in modulating osteogenic differentiation by specifically downregulating Wnt antagonist DKK1.
Academic Article Epigenetic regulation of early osteogenesis and mineralized tissue formation by a HOXA10-PBX1-associated complex.
Academic Article Runx2 protein expression utilizes the Runx2 P1 promoter to establish osteoprogenitor cell number for normal bone formation.
Academic Article Role of the WWOX tumor suppressor gene in bone homeostasis and the pathogenesis of osteosarcoma.
Academic Article Interaction of the 1alpha,25-dihydroxyvitamin D3 receptor at the distal promoter region of the bone-specific osteocalcin gene requires nucleosomal remodelling.
Academic Article Forum on aging and skeletal health: summary of the proceedings of an ASBMR workshop.
Academic Article MicroRNA control of bone formation and homeostasis.
Academic Article Control of mesenchymal lineage progression by microRNAs targeting skeletal gene regulators Trps1 and Runx2.
Academic Article The core-binding factor beta subunit is required for bone formation and hematopoietic maturation.
Academic Article Cbfbeta interacts with Runx2 and has a critical role in bone development.
Academic Article Transcriptional induction of the osteocalcin gene during osteoblast differentiation involves acetylation of histones h3 and h4.
Academic Article MicroRNA functions in osteogenesis and dysfunctions in osteoporosis.
Academic Article Regulation of the bone-specific osteocalcin gene by p300 requires Runx2/Cbfa1 and the vitamin D3 receptor but not p300 intrinsic histone acetyltransferase activity.
Academic Article Osteoblast-related transcription factors Runx2 (Cbfa1/AML3) and MSX2 mediate the expression of bone sialoprotein in human metastatic breast cancer cells.
Academic Article Runx1/AML1 hematopoietic transcription factor contributes to skeletal development in vivo.
Academic Article The Wnt antagonist secreted frizzled-related protein-1 is a negative regulator of trabecular bone formation in adult mice.
Academic Article Fidelity of Runx2 activity in breast cancer cells is required for the generation of metastases-associated osteolytic disease.
Academic Article Bone-specific transcription factor Runx2 interacts with the 1alpha,25-dihydroxyvitamin D3 receptor to up-regulate rat osteocalcin gene expression in osteoblastic cells.
Academic Article Dlx3 transcriptional regulation of osteoblast differentiation: temporal recruitment of Msx2, Dlx3, and Dlx5 homeodomain proteins to chromatin of the osteocalcin gene.
Academic Article SWI/SNF chromatin remodeling complex is obligatory for BMP2-induced, Runx2-dependent skeletal gene expression that controls osteoblast differentiation.
Academic Article The bone-specific expression of Runx2 oscillates during the cell cycle to support a G1-related antiproliferative function in osteoblasts.
Academic Article The Runx2 osteogenic transcription factor regulates matrix metalloproteinase 9 in bone metastatic cancer cells and controls cell invasion.
Academic Article The bone-related Zn finger transcription factor Osterix promotes proliferation of mesenchymal cells.
Academic Article Osteoblast differentiation and skeletal development are regulated by Mdm2-p53 signaling.
Academic Article Chromatin remodeling and transcriptional activity of the bone-specific osteocalcin gene require CCAAT/enhancer-binding protein beta-dependent recruitment of SWI/SNF activity.
Academic Article Reconstitution of Runx2/Cbfa1-null cells identifies a requirement for BMP2 signaling through a Runx2 functional domain during osteoblast differentiation.
Academic Article BMP2 commitment to the osteogenic lineage involves activation of Runx2 by DLX3 and a homeodomain transcriptional network.
Academic Article Pharmacologic targeting of a stem/progenitor population in vivo is associated with enhanced bone regeneration in mice.
Academic Article The WWOX tumor suppressor is essential for postnatal survival and normal bone metabolism.
Academic Article Specific residues of RUNX2 are obligatory for formation of BMP2-induced RUNX2-SMAD complex to promote osteoblast differentiation.
Academic Article Sustained and localized in vitro release of BMP-2/7, RANKL, and tetracycline from FlexBone, an elastomeric osteoconductive bone substitute.
Academic Article Enhanced fracture repair by leukotriene antagonism is characterized by increased chondrocyte proliferation and early bone formation: a novel role of the cysteinyl LT-1 receptor.
Academic Article SWI/SNF-independent nuclease hypersensitivity and an increased level of histone acetylation at the P1 promoter accompany active transcription of the bone master gene Runx2.
Academic Article Dicer inactivation in osteoprogenitor cells compromises fetal survival and bone formation, while excision in differentiated osteoblasts increases bone mass in the adult mouse.
Academic Article Metastatic bone disease: role of transcription factors and future targets.
Academic Article Arachidonic acid, eicosanoids, and fracture repair.
Academic Article The histone deacetylase inhibitor, vorinostat, reduces tumor growth at the metastatic bone site and associated osteolysis, but promotes normal bone loss.
Academic Article Suberoylanilide hydroxamic acid (SAHA; vorinostat) causes bone loss by inhibiting immature osteoblasts.
Academic Article Resolution of inflammation induces osteoblast function and regulates the Wnt signaling pathway.
Academic Article Genomic promoter occupancy of runt-related transcription factor RUNX2 in Osteosarcoma cells identifies genes involved in cell adhesion and motility.
Academic Article miRNA signatures associate with pathogenesis and progression of osteosarcoma.
Academic Article Vitamin K-dependent carboxylation of osteocalcin: friend or foe?
Academic Article Runx2 mediates epigenetic silencing of the bone morphogenetic protein-3B (BMP-3B/GDF10) in lung cancer cells.
Academic Article In vivo impact of Dlx3 conditional inactivation in neural crest-derived craniofacial bones.
Academic Article Runx2 protein represses Axin2 expression in osteoblasts and is required for craniosynostosis in Axin2-deficient mice.
Academic Article MicroRNA-34c inversely couples the biological functions of the runt-related transcription factor RUNX2 and the tumor suppressor p53 in osteosarcoma.
Academic Article Redefining the activity of a bone-specific transcription factor: novel insights for understanding bone formation.
Concept Bone Resorption
Concept Bone Development
Concept Bone Cysts, Aneurysmal
Concept Bone Diseases
Concept Bone Diseases, Developmental
Concept Bone Morphogenetic Protein 7
Concept Bone and Bones
Concept Fractures, Bone
Concept Bone Regeneration
Concept Bone Remodeling
Concept Bone Neoplasms
Concept Bone Density
Concept Bone Marrow Cells
Concept Bone Morphogenetic Proteins
Concept Bone Diseases, Metabolic
Concept Bone Morphogenetic Protein 2
Concept Bone Substitutes
Academic Article Integrin avß6 promotes an osteolytic program in cancer cells by upregulating MMP2.
Academic Article MicroRNAs in the control of metastatic bone disease.
Academic Article Runx2 is required for early stages of endochondral bone formation but delays final stages of bone repair in Axin2-deficient mice.
Academic Article The bone-specific Runx2-P1 promoter displays conserved three-dimensional chromatin structure with the syntenic Supt3h promoter.
Academic Article Disruption of crosstalk between mesenchymal stromal and tumor cells in bone marrow as a therapeutic target to prevent metastatic bone disease.
Academic Article Subnuclear domain proteins in cancer cells support the functions of RUNX2 in the DNA damage response.
Academic Article Runx2-Smad signaling impacts the progression of tumor-induced bone disease.
Academic Article Epigenetic pathways regulating bone homeostasis: potential targeting for intervention of skeletal disorders.
Academic Article Core binding factor ß of osteoblasts maintains cortical bone mass via stabilization of Runx2 in mice.
Academic Article Targeting of Runx2 by miR-135 and miR-203 Impairs Progression of Breast Cancer and Metastatic Bone Disease.
Academic Article Expression of the IL-11 Gene in Metastatic Cells Is Supported by Runx2-Smad and Runx2-cJun Complexes Induced by TGFß1.
Academic Article Core Binding Factor ß of Osteoblasts Maintains Cortical Bone Mass Via Stabilization of Runx2 in Mice.
Academic Article Epigenetic pathways regulating bone homeostasis.
Academic Article Non-coding RNAs: Epigenetic regulators of bone development and homeostasis.
Academic Article Epigenetic Control of the Bone-master Runx2 Gene during Osteoblast-lineage Commitment by the Histone Demethylase JARID1B/KDM5B.
Academic Article Epigenetic Modulation in Periodontitis: Interaction of Adiponectin and JMJD3-IRF4 Axis in Macrophages.
Academic Article Core Binding Factor ß of Osteoblasts Maintains Cortical Bone Mass via Stabilization of Runx2 in Mice.
Academic Article Antagonizing miR-218-5p attenuates Wnt signaling and reduces metastatic bone disease of triple negative breast cancer cells.
Academic Article Synovium-Derived MicroRNAs Regulate Bone Pathways in Rheumatoid Arthritis.
Academic Article Aneurysmal bone cysts and pathologic fracture associated with supernumerary ring chromosome 6 in two unrelated patients.
Academic Article Regulation of Bone Metabolism by Serotonin.
Academic Article Regulation of osteogenesis by long noncoding RNAs: An epigenetic mechanism contributing to bone formation.

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