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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Rheumatology and Inflammation Research at Sahlgrenska Academy, University of Göteborg, Göteborg, Sweden.
authors.forename: Malin C
authors.initials: MC
authors.lastname: Erlandsson
authors.affiliation: Department of Rheumatology and Inflammation Research at Sahlgrenska Academy, University of Göteborg, Göteborg, Sweden.
authors.forename: Mattias D
authors.initials: MD
authors.lastname: Svensson
authors.affiliation: Department of Rheumatology and Inflammation Research at Sahlgrenska Academy, University of Göteborg, Göteborg, Sweden.
authors.forename: Ing-Marie
authors.initials: IM
authors.lastname: Jonsson
authors.affiliation: Department of Rheumatology and Inflammation Research at Sahlgrenska Academy, University of Göteborg, Göteborg, Sweden.
authors.forename: Li
authors.initials: L
authors.lastname: Bian
authors.affiliation: Cancer Research Institute, Copenhagen, Denmark.
authors.forename: Noona
authors.initials: N
authors.lastname: Ambartsumian
authors.affiliation: Department of Rheumatology and Inflammation Research at Sahlgrenska Academy, University of Göteborg, Göteborg, Sweden.
authors.forename: Sofia
authors.initials: S
authors.lastname: Andersson
authors.affiliation: Pharmatest Service Ltd., Turku, Finland.
authors.forename: ZhiQi
authors.initials: Z
authors.lastname: Peng
authors.affiliation: Pharmatest Service Ltd., Turku, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Vääräniemi
authors.affiliation: Center for Bone and Arthritis Research at Sahlgrenska Academy, University of Göteborg, Göteborg, Sweden.
authors.forename: Claes
authors.initials: C
authors.lastname: Ohlsson
authors.affiliation: Department of Rheumatology and Inflammation Research at Sahlgrenska Academy, University of Göteborg, Göteborg, Sweden.
authors.forename: Karin M E
authors.initials: KME
authors.lastname: Andersson
authors.affiliation: Department of Rheumatology and Inflammation Research at Sahlgrenska Academy, University of Göteborg, Göteborg, Sweden. Electronic address: maria.bokarewa@rheuma.gu.se.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Bokarewa
mesh_terms: D000818:Animals; D016723:Bone Remodeling; D001862:Bone Resorption / Q000150:complications / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D002462:Cell Membrane / Q000378:metabolism; D048430:Cell Shape; D005109:Extracellular Matrix / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D009929:Organ Size; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology*; D010014:Osteolysis / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000172:deficiency / Q000378:metabolism*
chemical_list: D016023:Integrins; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; D020782:Matrix Metalloproteinases
keywords: Adhesion molecules; Bone; Cathepsin K; Osteoclasts; Osteopetrosis; S100A4