Dataset Information

E-selectin ligand 1 regulates bone remodeling by limiting bioactive TGF-? in the bone microenvironment.

ABSTRACT: TGF-? is abundantly produced in the skeletal system and plays a crucial role in skeletal homeostasis. E-selectin ligand-1 (ESL-1), a Golgi apparatus-localized protein, acts as a negative regulator of TGF-? bioavailability by attenuating maturation of pro-TGF-? during cartilage homeostasis. However, whether regulation of intracellular TGF-? maturation by ESL-1 is also crucial during bone homeostasis has not been well defined. Here, we show that Esl-1(-/-) mice exhibit a severe osteopenia with elevated bone resorption and decreased bone mineralization. In primary culture, Esl-1(-/-) osteoclast progenitors show no difference in osteoclastogenesis. However, Esl-1(-/-) osteoblasts show delayed differentiation and mineralization and stimulate osteoclastogenesis more potently in the osteoblast-osteoclast coculture, suggesting that ESL-1 primarily acts in osteoblasts to regulate bone homeostasis. In addition, Esl-1(-/-) calvaria exhibit an elevated mature TGF-?/pro-TGF-? ratio, with increased expression of TGF-? downstream targets (plasminogen activator inhibitor-1, parathyroid hormone-related peptide, connective tissue growth factor, and matrix metallopeptidase 13, etc.) and a key regulator of osteoclastogenesis (receptor activator of nuclear factor ?B ligand). Moreover, in vivo treatment with 1D11, a pan-TGF-? antibody, significantly improved the low bone mass of Esl-1(-/-) mice, suggesting that elevated TGF-? signaling is the major cause of osteopenia in Esl-1(-/-) mice. In summary, our study identifies ESL-1 as an important regulator of bone remodeling and demonstrates that the modulation of TGF-? maturation is pivotal in the maintenance of a homeostatic bone microenvironment and for proper osteoblast-osteoclast coupling.

SUBMITTER: Yang T

PROVIDER: S-EPMC3645519 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

E-selectin ligand 1 regulates bone remodeling by limiting bioactive TGF-β in the bone microenvironment.

Yang Tao T Grafe Ingo I Bae Yangjin Y Chen Shan S Chen Yuqing Y Bertin Terry K TK Jiang Ming-Ming MM Ambrose Catherine G CG Lee Brendan B

Proceedings of the National Academy of Sciences of the United States of America 20130415 18

TGF-β is abundantly produced in the skeletal system and plays a crucial role in skeletal homeostasis. E-selectin ligand-1 (ESL-1), a Golgi apparatus-localized protein, acts as a negative regulator of TGF-β bioavailability by attenuating maturation of pro-TGF-β during cartilage homeostasis. However, whether regulation of intracellular TGF-β maturation by ESL-1 is also crucial during bone homeostasis has not been well defined. Here, we show that Esl-1(-/-) mice exhibit a severe osteopenia with ele ...[more]

PMID: 23589896

Similar Datasets

Project description:Research backgroundThe role of osteocytes in maintaining bone mass has been progressively emphasized. Pip5k1c is the most critical isoform among PIP5KIs, which can regulate cytoskeleton, biomembrane, and Ca2+ release of cells and participate in many processes, such as cell adhesion, differentiation, and apoptosis. However, its expression and function in osteocytes are still unclear.Materials and methodsTo determine the function of Pip5k1c in osteocytes, the expression of Pip5k1c in osteocytes was deleted by breeding the 10-kb mouse Dmp1-Cre transgenic mice with the Pip5k1cfl/fl mice. Bone histomorphometry, micro-computerized tomography analysis, immunofluorescence staining and western blotting were used to determine the effects of Pip5k1c loss on bone mass. In vitro, we explored the mechanism by siRNA knockdown of Pip5k1c in MLO-Y4 cells.ResultsPip5k1c expression was decreased in osteocytes in senescent and osteoporotic tissues both in humans and mice. Loss of Pip5k1c in osteocytes led to a low bone mass in long bones and spines and impaired biomechanical properties in femur, without changes in calvariae. The loss of Pip5k1c resulted in the reduction of the protein level of type 1 collagen in tibiae and MLO-Y4 cells. Osteocyte Pip5k1c loss reduced the osteoblast and bone formation rate with high expression of sclerostin, impacting the osteoclast activities at the same time. Moreover, Pip5k1c loss in osteocytes reduced expression of focal adhesion proteins and promoted apoptosis.ConclusionOur studies demonstrate the critical role and mechanism of Pip5k1c in osteocytes in regulating bone remodeling.The translational potential of this articleOsteocyte has been considered to a key role in regulating bone homeostasis. The present study has demonstrated that the significance of Pip5k1c in bone homeostasis by regulating the expression of collagen, sclerostin and focal adhesion expression, which provided a possible therapeutic target against human metabolic bone disease.

Dataset Information

E-selectin ligand 1 regulates bone remodeling by limiting bioactive TGF-? in the bone microenvironment.

Publications

E-selectin ligand 1 regulates bone remodeling by limiting bioactive TGF-β in the bone microenvironment.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets