Expression of metastasin S100A4 is essential for bone resorption and regulates osteoclast function

Malin C Erlandsson; M Svensson; Ing-Marie Jonsson; Li Bian; Noona Ambartsumian; Sofia Andersson; Zhiqi Peng; Jukka Vääräniemi; Claes Ohlsson; Karin M E Andersson; Maria I Bokarewa

doi:10.1016/j.bbamcr.2013.06.020

Expression of metastasin S100A4 is essential for bone resorption and regulates osteoclast function

Malin C Erlandsson, M Svensson, Ing-Marie Jonsson, Li Bian, Noona Ambartsumian, Sofia Andersson, Zhiqi Peng, Jukka Vääräniemi, Claes Ohlsson, Karin M E Andersson, Maria I Bokarewa

20 Citations (Scopus)

Abstract

Objective: S100A4 is a Ca-binding protein that regulates cell growth, survival, and motility. The abundant expression of S100A4 in rheumatiod arthritis contributes to the invasive growth of joint tissue and to bone damage. In the present study, we analysed the role of S100A4 in bone homeostasis. Methods: Peripheral quantitative computed tomography and histomorphometric analysis were performed in mice lacking the entire S100A4 protein (S100A4KO) and in wild-type (WT) counterparts treated with shRNA-lentiviral constructs targeting S100A4 (S100A4-shRNA). Control groups consisted of sex-matched WT counterparts and WT mice treated with a non-targeting RNA construct. Results: S100A4 deficiency was associated with higher trabecular and cortical bone mass, increased number and thickness of trabeculi combined with larger periosteal circumference and higher predicted bone strength. S100A4 inhibition by shRNA led to an increase in cortical bone in WT mice. S100A4-deficieny was associated with a reduced number of functional osteoclasts. S100A4KO and S100A4-shRNA-treated bone marrow progenitors gave rise to a large number of small TRAP. + cells with few nuclei and few pseudopodial processes. Poor osteoclastogenesis and the low resorptive capacity in S100A4Ko mice may be linked to low levels of surface integrins, impaired adhesion capacity, and poor multinucleation in S100A4-deficient osteoclasts, as well as a low content of proteolytic enzymes cathepsin K and MMP3 and MMP9 to break down the organic matrix. Conclusion: S100A4 emerges as a negative regulator of bone metabolism potentially responsible for the excessive bone turnover in conditions marked by high levels of S100A4 protein, such as inflammation and rheumatoid arthritis.

Original language	English
Journal	BBA General Subjects
Volume	1833
Issue number	12
Pages (from-to)	2653-2663
Number of pages	11
ISSN	0304-4165
DOIs	https://doi.org/10.1016/j.bbamcr.2013.06.020
Publication status	Published - Dec 2013

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10.1016/j.bbamcr.2013.06.020

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@article{8925afc0fdd446919fbed25819cb3f4a,

title = "Expression of metastasin S100A4 is essential for bone resorption and regulates osteoclast function",

abstract = "Objective: S100A4 is a Ca-binding protein that regulates cell growth, survival, and motility. The abundant expression of S100A4 in rheumatiod arthritis contributes to the invasive growth of joint tissue and to bone damage. In the present study, we analysed the role of S100A4 in bone homeostasis. Methods: Peripheral quantitative computed tomography and histomorphometric analysis were performed in mice lacking the entire S100A4 protein (S100A4KO) and in wild-type (WT) counterparts treated with shRNA-lentiviral constructs targeting S100A4 (S100A4-shRNA). Control groups consisted of sex-matched WT counterparts and WT mice treated with a non-targeting RNA construct. Results: S100A4 deficiency was associated with higher trabecular and cortical bone mass, increased number and thickness of trabeculi combined with larger periosteal circumference and higher predicted bone strength. S100A4 inhibition by shRNA led to an increase in cortical bone in WT mice. S100A4-deficieny was associated with a reduced number of functional osteoclasts. S100A4KO and S100A4-shRNA-treated bone marrow progenitors gave rise to a large number of small TRAP. + cells with few nuclei and few pseudopodial processes. Poor osteoclastogenesis and the low resorptive capacity in S100A4Ko mice may be linked to low levels of surface integrins, impaired adhesion capacity, and poor multinucleation in S100A4-deficient osteoclasts, as well as a low content of proteolytic enzymes cathepsin K and MMP3 and MMP9 to break down the organic matrix. Conclusion: S100A4 emerges as a negative regulator of bone metabolism potentially responsible for the excessive bone turnover in conditions marked by high levels of S100A4 protein, such as inflammation and rheumatoid arthritis.",

author = "Erlandsson, {Malin C} and M Svensson and Ing-Marie Jonsson and Li Bian and Noona Ambartsumian and Sofia Andersson and Zhiqi Peng and Jukka V{\"a}{\"a}r{\"a}niemi and Claes Ohlsson and Andersson, {Karin M E} and Bokarewa, {Maria I}",

note = "{\textcopyright} 2013.",

year = "2013",

month = dec,

doi = "10.1016/j.bbamcr.2013.06.020",

language = "English",

volume = "1833",

pages = "2653--2663",

journal = "B B A - General Subjects",

issn = "0304-4165",

publisher = "Elsevier",

number = "12",

}

TY - JOUR

T1 - Expression of metastasin S100A4 is essential for bone resorption and regulates osteoclast function

AU - Erlandsson, Malin C

AU - Svensson, M

AU - Jonsson, Ing-Marie

AU - Bian, Li

AU - Ambartsumian, Noona

AU - Andersson, Sofia

AU - Peng, Zhiqi

AU - Vääräniemi, Jukka

AU - Ohlsson, Claes

AU - Andersson, Karin M E

AU - Bokarewa, Maria I

PY - 2013/12

Y1 - 2013/12

N2 - Objective: S100A4 is a Ca-binding protein that regulates cell growth, survival, and motility. The abundant expression of S100A4 in rheumatiod arthritis contributes to the invasive growth of joint tissue and to bone damage. In the present study, we analysed the role of S100A4 in bone homeostasis. Methods: Peripheral quantitative computed tomography and histomorphometric analysis were performed in mice lacking the entire S100A4 protein (S100A4KO) and in wild-type (WT) counterparts treated with shRNA-lentiviral constructs targeting S100A4 (S100A4-shRNA). Control groups consisted of sex-matched WT counterparts and WT mice treated with a non-targeting RNA construct. Results: S100A4 deficiency was associated with higher trabecular and cortical bone mass, increased number and thickness of trabeculi combined with larger periosteal circumference and higher predicted bone strength. S100A4 inhibition by shRNA led to an increase in cortical bone in WT mice. S100A4-deficieny was associated with a reduced number of functional osteoclasts. S100A4KO and S100A4-shRNA-treated bone marrow progenitors gave rise to a large number of small TRAP. + cells with few nuclei and few pseudopodial processes. Poor osteoclastogenesis and the low resorptive capacity in S100A4Ko mice may be linked to low levels of surface integrins, impaired adhesion capacity, and poor multinucleation in S100A4-deficient osteoclasts, as well as a low content of proteolytic enzymes cathepsin K and MMP3 and MMP9 to break down the organic matrix. Conclusion: S100A4 emerges as a negative regulator of bone metabolism potentially responsible for the excessive bone turnover in conditions marked by high levels of S100A4 protein, such as inflammation and rheumatoid arthritis.

AB - Objective: S100A4 is a Ca-binding protein that regulates cell growth, survival, and motility. The abundant expression of S100A4 in rheumatiod arthritis contributes to the invasive growth of joint tissue and to bone damage. In the present study, we analysed the role of S100A4 in bone homeostasis. Methods: Peripheral quantitative computed tomography and histomorphometric analysis were performed in mice lacking the entire S100A4 protein (S100A4KO) and in wild-type (WT) counterparts treated with shRNA-lentiviral constructs targeting S100A4 (S100A4-shRNA). Control groups consisted of sex-matched WT counterparts and WT mice treated with a non-targeting RNA construct. Results: S100A4 deficiency was associated with higher trabecular and cortical bone mass, increased number and thickness of trabeculi combined with larger periosteal circumference and higher predicted bone strength. S100A4 inhibition by shRNA led to an increase in cortical bone in WT mice. S100A4-deficieny was associated with a reduced number of functional osteoclasts. S100A4KO and S100A4-shRNA-treated bone marrow progenitors gave rise to a large number of small TRAP. + cells with few nuclei and few pseudopodial processes. Poor osteoclastogenesis and the low resorptive capacity in S100A4Ko mice may be linked to low levels of surface integrins, impaired adhesion capacity, and poor multinucleation in S100A4-deficient osteoclasts, as well as a low content of proteolytic enzymes cathepsin K and MMP3 and MMP9 to break down the organic matrix. Conclusion: S100A4 emerges as a negative regulator of bone metabolism potentially responsible for the excessive bone turnover in conditions marked by high levels of S100A4 protein, such as inflammation and rheumatoid arthritis.

U2 - 10.1016/j.bbamcr.2013.06.020

DO - 10.1016/j.bbamcr.2013.06.020

M3 - Journal article

C2 - 23830916

SN - 0304-4165

VL - 1833

SP - 2653

EP - 2663

JO - B B A - General Subjects

JF - B B A - General Subjects

IS - 12

ER -

Expression of metastasin S100A4 is essential for bone resorption and regulates osteoclast function

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