Ectonucleotide Pyrophosphatase/Phosphodiesterase-1 (ENPP1) Protein Regulates Osteoblast Differentiation

Nam, Hwa Kyung; Liu, Jin; Li, Yan; Kragor, Andrew; Hatch, Nan

doi:10.1074/jbc.m111.221689

Cited by 66 publications

(66 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Enpp1 is necessary for osteoblast differentiation and inhibits bone mineralization. 36 Furthermore, Enpp1 À / À mice displayed trabecular bone loss and hyper-mineralization in long bones. 17 Ibsp À / À mice displayed impaired bone growth and mineralization and dramatically reduced bone formation.…”

Section: Dlx5/dlx6mentioning

confidence: 99%

DLX3 regulates bone mass by targeting genes supporting osteoblast differentiation and mineral homeostasis in vivo

Isaac

Gordon

et al. 2014

Cell Death Differ

View full text Add to dashboard Cite

Human mutations and in vitro studies indicate that DLX3 has a crucial function in bone development, however, the in vivo role of DLX3 in endochondral ossification has not been established. Here, we identify DLX3 as a central attenuator of adult bone mass in the appendicular skeleton. Dynamic bone formation, histologic and micro-computed tomography analyses demonstrate that in vivo DLX3 conditional loss of function in mesenchymal cells (Prx1-Cre) and osteoblasts (OCN-Cre) results in increased bone mass accrual observed as early as 2 weeks that remains elevated throughout the lifespan owing to increased osteoblast activity and increased expression of bone matrix genes. Dlx3OCN-conditional knockout mice have more trabeculae that extend deeper in the medullary cavity and thicker cortical bone with an increased mineral apposition rate, decreased bone mineral density and increased cortical porosity. Trabecular TRAP staining and site-specific Q-PCR demonstrated that osteoclastic resorption remained normal on trabecular bone, whereas cortical bone exhibited altered osteoclast patterning on the periosteal surface associated with high Opg/Rankl ratios. Using RNA sequencing and chromatin immunoprecipitation-Seq analyses, we demonstrate that DLX3 regulates transcription factors crucial for bone formation such as Dlx5, Dlx6, Runx2 and Sp7 as well as genes important to mineral deposition (Ibsp, Enpp1, Mepe) and bone turnover (Opg). Furthermore, with the removal of DLX3, we observe increased occupancy of DLX5, as well as increased and earlier occupancy of RUNX2 on the bone-specific osteocalcin promoter. Together, these findings provide novel insight into mechanisms by which DLX3 attenuates bone mass accrual to support bone homeostasis by osteogenic gene pathway regulation. Endochondral bone formation (EBF) and homeostasis require a regulated program of mesenchymal condensation, chondrocyte differentiation, vascular invasion, cartilage resorption, osteoprogenitor recruitment and differentiation and bone remodeling. These key processes are under the control of essential bone transcription factors (TFs), including RUNX2, SP7 and homeodomain protein families such as HOX, MSX and DLX.1-3 DLX proteins are important regulators of developmental and differentiation processes, including skeletal development. [4][5][6] A missense mutation in DLX5 leads to split hand and foot malformation 7 and DLX5 and DLX6 are positive transcriptional regulators of osteochondroblastic differentiation. 6 DLX3 is defined as an osteogenic regulator, as human mutations in DLX3 lead to tricho-dento-osseous (TDO) syndrome, an ectodermal dysplasia that causes increased bone mineral density (BMD) in intramembranous and endochondral bones. In vitro, osteocalcin (Ocn), Runx2 9,10 and osteoactivin [9][10][11] are directly regulated by DLX3, and overexpression of DLX3 in osteoprogenitors stimulates transcription of osteogenic markers. 9Recently, we investigated the effects of neural crest deletion of Dlx3 in craniofacial bones. 12 The gene signature of craniofacial...

show abstract

Section: Dlx5/dlx6mentioning

confidence: 99%

DLX3 regulates bone mass by targeting genes supporting osteoblast differentiation and mineral homeostasis in vivo

Isaac

Gordon

et al. 2014

Cell Death Differ

View full text Add to dashboard Cite

show abstract

“…Indeed, patients with recessive ENPP1 mutations have iFGF23 modestly above the normal mean as well as hypophosphatemia (61,62). Evidence supports that ENPP1 may regulate osteoblastic differentiation in an manner independent of extracellular phosphate (Figure 1) (63). Therefore, the ENPP1 ARHR-2 mutations could potentially result in a cell differentiation defect and over expression of FGF23, similar to the biological situation for DMP1 (ARHR-1) and PHEX (XLH).…”

Section: Autosomal Recessive Hypophosphatemic Rickets (Arhr)mentioning

confidence: 77%

Hypophosphatemic Rickets: Revealing Novel Control Points for Phosphate Homeostasis

White

Hum

Econs

2014

Curr Osteoporos Rep

View full text Add to dashboard Cite

Rapid and somewhat surprising advances have recently been made towards understanding the molecular mechanisms causing heritable disorders of hypophosphatemia. The results of clinical, genetic, and translational studies have interwoven novel concepts underlying the endocrine control of phosphate metabolism, with far-reaching implications for treatment of both rare, Mendelian diseases as well as common disorders of blood phosphate excess such as chronic kidney disease (CKD). In particular, diseases caused by changes in the expression and proteolytic control of the phosphaturic hormone Fibroblast growth factor-23 (FGF23) have come to the forefront in terms of directing new models explaining mineral metabolism. These hypophosphatemic disorders, as well as others resulting from independent defects in phosphate transport or metabolism, will be reviewed herein, and implications for emerging therapeutic strategies based upon these new findings will be discussed.

show abstract

“…This is supported by recent publications dem onstrating the regulatory role of bPPi on bone turnover based on controlling differentiation of osteoclast and os teoblast progenitor cells. 10,16 The 18 F-fluoride PET/CT scans were used to refine localization of bone growth. The images revealed bone formation within the entire implant site, as well as in the central part of the implant.…”

Section: Discussionmentioning

confidence: 99%

Development of a bioactive implant for repair and potential healing of cranial defects

Engstrand¹,

Kihlström²,

Neovius³

et al. 2014

JNS

View full text Add to dashboard Cite

The repair of complex craniofacial bone defects is challenging and a successful result is dependent on the size of the defect, quality of the soft tissue covering the defect, and choice of reconstruction method. The objective of this study was to develop a bioactive cranial implant that could provide a permanent reconstructive solution to the patient by stimulating bone healing of the defect. In this paper the authors report on the feasibility and clinical results of using such a newly developed device for the repair of a large traumatic and therapyresistant cranial bone defect. The patient had undergone numerous attempts at repair, in which established methods had been tried without success. 273Abbreviations used in this paper: bPPi = bcalcium pyrophos phates; bTCP = btricalcium phosphate.

show abstract

Ectonucleotide Pyrophosphatase/Phosphodiesterase-1 (ENPP1) Protein Regulates Osteoblast Differentiation

Cited by 66 publications

References 51 publications

DLX3 regulates bone mass by targeting genes supporting osteoblast differentiation and mineral homeostasis in vivo

DLX3 regulates bone mass by targeting genes supporting osteoblast differentiation and mineral homeostasis in vivo

Hypophosphatemic Rickets: Revealing Novel Control Points for Phosphate Homeostasis

Development of a bioactive implant for repair and potential healing of cranial defects

Contact Info

Product

Resources

About