E-selectin ligand-1 regulates growth plate homeostasis in mice by inhibiting the intracellular processing and secretion of mature TGF-β

Tao Yang, Roberto Mendoza-Londono, Huifang Lu, Jianning Tao, Kaiyi Li, Bettina Keller, Ming Ming Jiang, Rina Shah, Yuqing Chen, Terry K. Bertin, Feyza Engin, Branka Dabovic, Daniel B. Rifkin, John Hicks, Milan Jamrich, Arthur L. Beaudet, Brendan Lee

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

The majority of human skeletal dysplasias are caused by dysregulation of growth plate homeostasis. As TGF-β signaling is a critical determinant of growth plate homeostasis, skeletal dysplasias are often associated with dysregulation of this pathway. The context-dependent action of TFG-β signaling is tightly controlled by numerous mechanisms at the extracellular level and downstream of ligand-receptor interactions. However, TGF-β is synthesized as an inactive precursor that is cleaved to become mature in the Golgi apparatus, and the regulation of this posttranslational intracellular processing and trafficking is much less defined. Here, we report that a cysteine-rich protein, E-selectin ligand-1 (ESL-1), acts as a negative regulator of TGF-β production by binding TGF-β precursors in the Golgi apparatus in a cell-autonomous fashion, inhibiting their maturation. Furthermore, ESL-1 inhibited the processing of proTGF-β by a furin-like protease, leading to reduced secretion of mature TGF-β by primary mouse chondrocytes and HEK293 cells. In vivo loss of Esl1 in mice led to increased TGF-β/SMAD signaling in the growth plate that was associated with reduced chondrocyte proliferation and delayed terminal differentiation. Gain-of-function and rescue studies of the Xenopus ESL-1 ortholog in the context of early embryogenesis showed that this regulation of TGF-β/Nodal signaling was evolutionarily conserved. This study identifies what we believe to be a novel intracellular mechanism for regulating TGF-β during skeletal development and homeostasis.

Original languageEnglish (US)
Pages (from-to)2474-2485
Number of pages12
JournalJournal of Clinical Investigation
Volume120
Issue number7
DOIs
StatePublished - Jul 1 2010

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Growth Plate
Homeostasis
Golgi Apparatus
Chondrocytes
Furin
HEK293 Cells
Xenopus
Embryonic Development
Cysteine
Peptide Hydrolases
Ligands
cysteine-rich fibroblast growth factor receptor
Proteins

ASJC Scopus subject areas

  • Medicine(all)

Cite this

E-selectin ligand-1 regulates growth plate homeostasis in mice by inhibiting the intracellular processing and secretion of mature TGF-β. / Yang, Tao; Mendoza-Londono, Roberto; Lu, Huifang; Tao, Jianning; Li, Kaiyi; Keller, Bettina; Jiang, Ming Ming; Shah, Rina; Chen, Yuqing; Bertin, Terry K.; Engin, Feyza; Dabovic, Branka; Rifkin, Daniel B.; Hicks, John; Jamrich, Milan; Beaudet, Arthur L.; Lee, Brendan.

In: Journal of Clinical Investigation, Vol. 120, No. 7, 01.07.2010, p. 2474-2485.

Research output: Contribution to journalArticle

Yang, T, Mendoza-Londono, R, Lu, H, Tao, J, Li, K, Keller, B, Jiang, MM, Shah, R, Chen, Y, Bertin, TK, Engin, F, Dabovic, B, Rifkin, DB, Hicks, J, Jamrich, M, Beaudet, AL & Lee, B 2010, 'E-selectin ligand-1 regulates growth plate homeostasis in mice by inhibiting the intracellular processing and secretion of mature TGF-β', Journal of Clinical Investigation, vol. 120, no. 7, pp. 2474-2485. https://doi.org/10.1172/JCI42150
Yang, Tao ; Mendoza-Londono, Roberto ; Lu, Huifang ; Tao, Jianning ; Li, Kaiyi ; Keller, Bettina ; Jiang, Ming Ming ; Shah, Rina ; Chen, Yuqing ; Bertin, Terry K. ; Engin, Feyza ; Dabovic, Branka ; Rifkin, Daniel B. ; Hicks, John ; Jamrich, Milan ; Beaudet, Arthur L. ; Lee, Brendan. / E-selectin ligand-1 regulates growth plate homeostasis in mice by inhibiting the intracellular processing and secretion of mature TGF-β. In: Journal of Clinical Investigation. 2010 ; Vol. 120, No. 7. pp. 2474-2485.
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AU - Tao, Jianning

AU - Li, Kaiyi

AU - Keller, Bettina

AU - Jiang, Ming Ming

AU - Shah, Rina

AU - Chen, Yuqing

AU - Bertin, Terry K.

AU - Engin, Feyza

AU - Dabovic, Branka

AU - Rifkin, Daniel B.

AU - Hicks, John

AU - Jamrich, Milan

AU - Beaudet, Arthur L.

AU - Lee, Brendan

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