Global gene profiling reveals a downregulation of BMP gene expression in experimental atrophic nonunions compared to standard healing fractures

Niikura, Takahiro; Hak, David J.; Reddi, A. Hari

doi:10.1002/jor.20182

Cited by 110 publications

(89 citation statements)

References 27 publications

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“…Dentonin, which is the same as AC-100, promotes dental pulp stem cell proliferation in response to the dentin repair response (34,35). Furthermore, Bmp-2, Dlx5, and Mepe expressions are increased during healing of a bone fracture (36). Our data suggest that BMP-2-induced Mepe and Phex expression are much higher in the early differentiation stage than in the late differentiation stage (Fig.…”

Section: Mepe Expression Is Strongly Stimulated By Bmp-2 Treatment Anmentioning

confidence: 58%

Molecular Regulation of Matrix Extracellular Phosphoglycoprotein Expression by Bone Morphogenetic Protein-2

Cho¹,

Yoon²,

Woo³

et al. 2009

Journal of Biological Chemistry

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Matrix extracellular phosphoglycoprotein (MEPE) is mainly expressed in mineralizing tissues, and its C-terminal proteolytic cleavage product is an acidic-serine-asparate-rich-MEPE-associated motif (ASARM) that is a strong regulator of body phosphate metabolism and mineralization. There is sufficient data supporting a role for MEPE protein function in mineralization, however, little is known about the regulation of MEPE gene expression. As bone morphogenetic protein-2 (BMP-2) is one of the most important signals for calvarial mineralization and MEPE expression is higher in mineralized tissues, we attempted to uncover a regulatory circuit between BMP-2 and MEPE expression. Mepe expression is very low in proliferating MC3T3-E1 cells, but is dramatically increased in the mineralization stage and is strongly stimulated by treatment with BMP-2, even in proliferating cells. Overexpression and knockdown experiments of Smads, Dlx5, and Runx2 indicated that they are indispensable mediators of BMP-2-induced Mepe expression. In contrast, Msx2 showed strong inhibition of Mepe transcription. PHEX is an enzyme that prevents the release of the ASARM motif, a mineralization inhibitor, from the MEPE molecule. Thus, the MEPE/PHEX ratio may be a good indicator of mineralization progression because we found that the mRNA ratio and protein levels were low when osteoblasts were actively differentiating to the mineralization stage and the ratio was high when the cells reached the mineralization stage when it is assumed that osteocytes may protect themselves and make a space to survive from the mineralized matrix by releasing the ASARM motif. Collectively, MEPE expression is bone cell-specific and induced by the BMP-2 signaling pathway. In addition, the MEPE/PHEX ratio of the cell could be a very important barometer indicating the progression of tissue mineralization.Mineral homeostasis in the body is critical for healthy bones and teeth, and is generally regulated by the calcium-phosphate balance in the bone and kidney networks. In the past, the vitamin D/parathyroid hormone axis was assumed to be a single major circuit in bone-renal phosphate regulation, but recently, new bone-renal phosphate regulating factors have been identified. The finding of fibroblast growth factor 23 (FGF23), 2 phosphate-regulating genes with homologies to endopeptidases on the X chromosome (PHEX) and matrix extracellular phosphoglycoprotein (MEPE) genes, and their pathophysiological roles in the genetic diseases of mineral metabolism, have provided a great deal of insight into the understanding of bone-and mineral-related diseases. Among these, autosomal-dominant hypophosphatemic rickets (OMIM number 193100) is characterized by renal phosphate wasting, hypophosphatemia, and inappropriately normal 1,25-dihydroxyvitamin D 3 levels (1). Autosomal-dominant hypophosphatemic rickets is caused by a missense mutation of FGF23, which is resistant to proteolysis by PHEX and increases the half-life of full-length phosphaturic FGF23 (2). Second, X-linked hypophosphatemic...

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Section: Mepe Expression Is Strongly Stimulated By Bmp-2 Treatment Anmentioning

confidence: 58%

Molecular Regulation of Matrix Extracellular Phosphoglycoprotein Expression by Bone Morphogenetic Protein-2

Cho¹,

Yoon²,

Woo³

et al. 2009

Journal of Biological Chemistry

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“…b-Actin was used as an internal control. Relative mRNA expression levels were calculated as described by Niikura et al 18 PCR primers were as follows:…”

Section: Microarray Analysismentioning

confidence: 99%

Human mesenchymal stem cells in synovial fluid increase in the knee with degenerated cartilage and osteoarthritis

Sekiya

Ojima

Suzuki

et al. 2011

Journal Orthopaedic Research

190

174

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We investigated whether mesenchymal stem cells (MSCs) in synovial fluid (SF) increased in the knee with degenerated cartilage and osteoarthritis. SF was obtained from the knee joints of 22 patients with anterior cruciate ligament (ACL) injury during ACL reconstruction, and cartilage degeneration was evaluated arthroscopically. SF was also obtained from the knee joints of 6 healthy volunteers, 20 patients with mild osteoarthritis, and 26 patients with severe osteoarthritis, in which the grading was evaluated radiographically. The cell component in the SF was cultured for analyses. Synovium (SYN) and bone marrow (BM) were also harvested during total knee arthroplasties. The MSC number in SF was correlated with the cartilage degeneration score evaluated by arthroscopy. The MSC number in the SF was hardly noticed in normal volunteers, but it increased in accordance with the grading of osteoarthritis. Though no significant differences were observed regarding surface epitopes, or differentiation potentials, the morphology and gene profiles in SF MSCs were more similar to those in SYN MSCs than in BM MSCs. We listed 20 genes which were expressed higher in both SYN MSCs and SF MSCs than in BM MSCs, and 3 genes were confirmed by quantitative RT-PCR. MSCs in SF increased along with degenerated cartilage and osteoarthritis. ß

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“…1 By microarray technology the gene expression profiles of BMPs and their antagonists were investigated in standard healing fractures and atrophic nonunions produced by periosteal cauterization at the fracture site. 2 It was shown that the expression of several BMPs and their antagonists was significantly lower in nonunions compared to standard healing fractures. 2 Angiogenesis, the formation of new blood vessels from pre-existing ones, is promoted after fracture to maintain oxygen homeostasis, deliver nutrients, remove waste products, and provide cells and biological mediators.…”

mentioning

confidence: 99%

“…2 It was shown that the expression of several BMPs and their antagonists was significantly lower in nonunions compared to standard healing fractures. 2 Angiogenesis, the formation of new blood vessels from pre-existing ones, is promoted after fracture to maintain oxygen homeostasis, deliver nutrients, remove waste products, and provide cells and biological mediators. Furthermore, angiogenesis plays a pivotal role during intramembranous bone formation and endochondral ossification.…”

mentioning

confidence: 99%

Differential regulation of blood vessel formation between standard and delayed bone healing

Lienau

Schmidt‐Bleek

Peters

et al. 2009

Journal Orthopaedic Research

122

120

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Blood vessel formation is a prerequisite for bone healing. In this study, we tested the hypothesis that a delay in bone healing is associated with an altered regulation of blood vessel formation. A tibial osteotomy was performed in two groups of sheep and stabilized with either a rigid external fixator leading to standard healing or with a highly rotationally unstable one leading to delayed healing. At days 4, 7, 9, 11, 14, 21, and 42 after surgery, total RNA was extracted from the callus. Gene expressions of vWF, an endothelial cell marker, and of several molecules related to blood vessel formation were studied by qPCR. Furthermore, histology was performed on fracture hematoma and callus sections. Histologically, the first blood vessels were detected at day 7 in both groups. mRNA expression levels of vWF, Ang1, Ang2, VEGF, CYR61, FGF2, MMP2, and TIMP1 were distinctly lower in the delayed compared to the standard healing group at several time points. Based on differential expression patterns, days 7 and 21 postoperatively were revealed to be essential time points for vascularization of the ovine fracture callus. This work demonstrates for the first time a differential regulation of blood vessel formation between standard and mechanically induced delayed healing in a sheep osteotomy model. ß

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Global gene profiling reveals a downregulation of BMP gene expression in experimental atrophic nonunions compared to standard healing fractures

Cited by 110 publications

References 27 publications

Molecular Regulation of Matrix Extracellular Phosphoglycoprotein Expression by Bone Morphogenetic Protein-2

Molecular Regulation of Matrix Extracellular Phosphoglycoprotein Expression by Bone Morphogenetic Protein-2

Human mesenchymal stem cells in synovial fluid increase in the knee with degenerated cartilage and osteoarthritis

Differential regulation of blood vessel formation between standard and delayed bone healing

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