Osteoblast derived-neurotrophin‑3 induces cartilage removal proteases and osteoclast-mediated function at injured growth plate in rats

Yu Wen Su, Shek Man Chim, Lin Zhou, Mohammadhossein Hassanshahi, Rosa Chung, Chiaming Fan, Yunmei Song, Bruce K. Foster, Clive A. Prestidge, Yaser Peymanfar, Qian Tang, Lisa M. Butler, Stan Gronthos, Di Chen, Yangli Xie, Lin Chen, Xin Fu Zhou, Jiake Xu, Cory J. Xian

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Faulty bony repair causes dysrepair of injured growth plate cartilage and bone growth defects in children; however, the underlying mechanisms are unclear. Recently, we observed the prominent induction of neurotrophin‑3 (NT-3) and its important roles as an osteogenic and angiogenic factor promoting the bony repair. The current study investigated its roles in regulating injury site remodelling. In a rat tibial growth plate drill-hole injury repair model, NT-3 was expressed prominently in osteoblasts at the injury site. Recombinant NT-3 (rhNT-3) systemic treatment enhanced, but NT-3 immunoneutralization attenuated, expression of cartilage-removal proteases (MMP-9 and MMP-13), presence of bone-resorbing osteoclasts and expression of osteoclast protease cathepsin K, and remodelling at the injury site. NT-3 was also highly induced in cultured mineralizing rat bone marrow stromal cells, and the conditioned medium augmented osteoclast formation and resorptive activity, an ability that was blocked by presence of anti-NT-3 antibody. Moreover, NT-3 and receptor TrkC were induced during osteoclastogenesis, and rhNT-3 treatment activated TrkC downstream kinase Erk1/2 in differentiating osteoclasts although rhNT-3 alone did not affect activation of osteoclastogenic transcription factors NF-κB or NFAT in RAW264.7 osteoclast precursor cells. Furthermore, rhNT-3 treatment increased, but NT-3 neutralization reduced, expression of osteoclastogenic cytokines (RANKL, TNF-α and IL-1) in mineralizing osteoblasts and in growth plate injury site, and rhNT-3 augmented the induction of these cytokines caused by RANKL treatment in RAW264.7 cells. Thus, injury site osteoblast-derived NT-3 is important in promoting growth plate injury site remodelling, as it induces cartilage proteases for cartilage removal and augments osteoclastogenesis and resorption both directly (involving activing Erk1/2 and substantiating RANKL-induced increased expression of osteoclastogenic signals in differentiating osteoclasts) and indirectly (inducing osteoclastogenic signals in osteoblasts).

Original languageEnglish
Pages (from-to)232-247
Number of pages16
JournalBone
Volume116
DOIs
Publication statusPublished - 1 Nov 2018

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Growth Plate
Osteoclasts
Osteoblasts
Cartilage
Peptide Hydrolases
Wounds and Injuries
Matrix Metalloproteinases
Osteogenesis
trkC Receptor
Cathepsin K
Cytokines
Endopeptidase K
Mandrillus
Angiogenesis Inducing Agents
Bone Development
Therapeutics
Conditioned Culture Medium
Mesenchymal Stromal Cells
Interleukin-1
Anti-Idiotypic Antibodies

Cite this

Su, Yu Wen ; Chim, Shek Man ; Zhou, Lin ; Hassanshahi, Mohammadhossein ; Chung, Rosa ; Fan, Chiaming ; Song, Yunmei ; Foster, Bruce K. ; Prestidge, Clive A. ; Peymanfar, Yaser ; Tang, Qian ; Butler, Lisa M. ; Gronthos, Stan ; Chen, Di ; Xie, Yangli ; Chen, Lin ; Zhou, Xin Fu ; Xu, Jiake ; Xian, Cory J. / Osteoblast derived-neurotrophin‑3 induces cartilage removal proteases and osteoclast-mediated function at injured growth plate in rats. In: Bone. 2018 ; Vol. 116. pp. 232-247.
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title = "Osteoblast derived-neurotrophin‑3 induces cartilage removal proteases and osteoclast-mediated function at injured growth plate in rats",
abstract = "Faulty bony repair causes dysrepair of injured growth plate cartilage and bone growth defects in children; however, the underlying mechanisms are unclear. Recently, we observed the prominent induction of neurotrophin‑3 (NT-3) and its important roles as an osteogenic and angiogenic factor promoting the bony repair. The current study investigated its roles in regulating injury site remodelling. In a rat tibial growth plate drill-hole injury repair model, NT-3 was expressed prominently in osteoblasts at the injury site. Recombinant NT-3 (rhNT-3) systemic treatment enhanced, but NT-3 immunoneutralization attenuated, expression of cartilage-removal proteases (MMP-9 and MMP-13), presence of bone-resorbing osteoclasts and expression of osteoclast protease cathepsin K, and remodelling at the injury site. NT-3 was also highly induced in cultured mineralizing rat bone marrow stromal cells, and the conditioned medium augmented osteoclast formation and resorptive activity, an ability that was blocked by presence of anti-NT-3 antibody. Moreover, NT-3 and receptor TrkC were induced during osteoclastogenesis, and rhNT-3 treatment activated TrkC downstream kinase Erk1/2 in differentiating osteoclasts although rhNT-3 alone did not affect activation of osteoclastogenic transcription factors NF-κB or NFAT in RAW264.7 osteoclast precursor cells. Furthermore, rhNT-3 treatment increased, but NT-3 neutralization reduced, expression of osteoclastogenic cytokines (RANKL, TNF-α and IL-1) in mineralizing osteoblasts and in growth plate injury site, and rhNT-3 augmented the induction of these cytokines caused by RANKL treatment in RAW264.7 cells. Thus, injury site osteoblast-derived NT-3 is important in promoting growth plate injury site remodelling, as it induces cartilage proteases for cartilage removal and augments osteoclastogenesis and resorption both directly (involving activing Erk1/2 and substantiating RANKL-induced increased expression of osteoclastogenic signals in differentiating osteoclasts) and indirectly (inducing osteoclastogenic signals in osteoblasts).",
keywords = "Growth plate injury, Injury site remodelling, Neurotrophic factors, Signal crosstalk",
author = "Su, {Yu Wen} and Chim, {Shek Man} and Lin Zhou and Mohammadhossein Hassanshahi and Rosa Chung and Chiaming Fan and Yunmei Song and Foster, {Bruce K.} and Prestidge, {Clive A.} and Yaser Peymanfar and Qian Tang and Butler, {Lisa M.} and Stan Gronthos and Di Chen and Yangli Xie and Lin Chen and Zhou, {Xin Fu} and Jiake Xu and Xian, {Cory J.}",
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Su, YW, Chim, SM, Zhou, L, Hassanshahi, M, Chung, R, Fan, C, Song, Y, Foster, BK, Prestidge, CA, Peymanfar, Y, Tang, Q, Butler, LM, Gronthos, S, Chen, D, Xie, Y, Chen, L, Zhou, XF, Xu, J & Xian, CJ 2018, 'Osteoblast derived-neurotrophin‑3 induces cartilage removal proteases and osteoclast-mediated function at injured growth plate in rats' Bone, vol. 116, pp. 232-247. https://doi.org/10.1016/j.bone.2018.08.010

Osteoblast derived-neurotrophin‑3 induces cartilage removal proteases and osteoclast-mediated function at injured growth plate in rats. / Su, Yu Wen; Chim, Shek Man; Zhou, Lin; Hassanshahi, Mohammadhossein; Chung, Rosa; Fan, Chiaming; Song, Yunmei; Foster, Bruce K.; Prestidge, Clive A.; Peymanfar, Yaser; Tang, Qian; Butler, Lisa M.; Gronthos, Stan; Chen, Di; Xie, Yangli; Chen, Lin; Zhou, Xin Fu; Xu, Jiake; Xian, Cory J.

In: Bone, Vol. 116, 01.11.2018, p. 232-247.

Research output: Contribution to journalArticle

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T1 - Osteoblast derived-neurotrophin‑3 induces cartilage removal proteases and osteoclast-mediated function at injured growth plate in rats

AU - Su, Yu Wen

AU - Chim, Shek Man

AU - Zhou, Lin

AU - Hassanshahi, Mohammadhossein

AU - Chung, Rosa

AU - Fan, Chiaming

AU - Song, Yunmei

AU - Foster, Bruce K.

AU - Prestidge, Clive A.

AU - Peymanfar, Yaser

AU - Tang, Qian

AU - Butler, Lisa M.

AU - Gronthos, Stan

AU - Chen, Di

AU - Xie, Yangli

AU - Chen, Lin

AU - Zhou, Xin Fu

AU - Xu, Jiake

AU - Xian, Cory J.

PY - 2018/11/1

Y1 - 2018/11/1

N2 - Faulty bony repair causes dysrepair of injured growth plate cartilage and bone growth defects in children; however, the underlying mechanisms are unclear. Recently, we observed the prominent induction of neurotrophin‑3 (NT-3) and its important roles as an osteogenic and angiogenic factor promoting the bony repair. The current study investigated its roles in regulating injury site remodelling. In a rat tibial growth plate drill-hole injury repair model, NT-3 was expressed prominently in osteoblasts at the injury site. Recombinant NT-3 (rhNT-3) systemic treatment enhanced, but NT-3 immunoneutralization attenuated, expression of cartilage-removal proteases (MMP-9 and MMP-13), presence of bone-resorbing osteoclasts and expression of osteoclast protease cathepsin K, and remodelling at the injury site. NT-3 was also highly induced in cultured mineralizing rat bone marrow stromal cells, and the conditioned medium augmented osteoclast formation and resorptive activity, an ability that was blocked by presence of anti-NT-3 antibody. Moreover, NT-3 and receptor TrkC were induced during osteoclastogenesis, and rhNT-3 treatment activated TrkC downstream kinase Erk1/2 in differentiating osteoclasts although rhNT-3 alone did not affect activation of osteoclastogenic transcription factors NF-κB or NFAT in RAW264.7 osteoclast precursor cells. Furthermore, rhNT-3 treatment increased, but NT-3 neutralization reduced, expression of osteoclastogenic cytokines (RANKL, TNF-α and IL-1) in mineralizing osteoblasts and in growth plate injury site, and rhNT-3 augmented the induction of these cytokines caused by RANKL treatment in RAW264.7 cells. Thus, injury site osteoblast-derived NT-3 is important in promoting growth plate injury site remodelling, as it induces cartilage proteases for cartilage removal and augments osteoclastogenesis and resorption both directly (involving activing Erk1/2 and substantiating RANKL-induced increased expression of osteoclastogenic signals in differentiating osteoclasts) and indirectly (inducing osteoclastogenic signals in osteoblasts).

AB - Faulty bony repair causes dysrepair of injured growth plate cartilage and bone growth defects in children; however, the underlying mechanisms are unclear. Recently, we observed the prominent induction of neurotrophin‑3 (NT-3) and its important roles as an osteogenic and angiogenic factor promoting the bony repair. The current study investigated its roles in regulating injury site remodelling. In a rat tibial growth plate drill-hole injury repair model, NT-3 was expressed prominently in osteoblasts at the injury site. Recombinant NT-3 (rhNT-3) systemic treatment enhanced, but NT-3 immunoneutralization attenuated, expression of cartilage-removal proteases (MMP-9 and MMP-13), presence of bone-resorbing osteoclasts and expression of osteoclast protease cathepsin K, and remodelling at the injury site. NT-3 was also highly induced in cultured mineralizing rat bone marrow stromal cells, and the conditioned medium augmented osteoclast formation and resorptive activity, an ability that was blocked by presence of anti-NT-3 antibody. Moreover, NT-3 and receptor TrkC were induced during osteoclastogenesis, and rhNT-3 treatment activated TrkC downstream kinase Erk1/2 in differentiating osteoclasts although rhNT-3 alone did not affect activation of osteoclastogenic transcription factors NF-κB or NFAT in RAW264.7 osteoclast precursor cells. Furthermore, rhNT-3 treatment increased, but NT-3 neutralization reduced, expression of osteoclastogenic cytokines (RANKL, TNF-α and IL-1) in mineralizing osteoblasts and in growth plate injury site, and rhNT-3 augmented the induction of these cytokines caused by RANKL treatment in RAW264.7 cells. Thus, injury site osteoblast-derived NT-3 is important in promoting growth plate injury site remodelling, as it induces cartilage proteases for cartilage removal and augments osteoclastogenesis and resorption both directly (involving activing Erk1/2 and substantiating RANKL-induced increased expression of osteoclastogenic signals in differentiating osteoclasts) and indirectly (inducing osteoclastogenic signals in osteoblasts).

KW - Growth plate injury

KW - Injury site remodelling

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