The activin A-follistatin system: potent regulator of human extracellular matrix mineralization.
Bone quality is an important determinant of osteoporosis, and proper osteoblast differentiation plays an important role in the control and maintenance of bone quality. We investigated the impact of activin signaling on human osteoblast differentiation, extracellular matrix formation, and mineralization. Activins belong to the transforming growth factor-beta superfamily and activin A treatment strongly inhibited mineralization in osteoblast cultures, whereas the activin antagonist follistatin increased mineralization. Osteoblasts produced activin A and follistatin in a differentiation-dependent manner, leading to autocrine regulation of extracellular matrix formation and mineralization. In addition, mineralization in a vascular smooth muscle cell-based model for pathological calcification was inhibited. Comparative activin A and follistatin gene expression profiling showed that activin signaling changes the expression of a specific range of extracellular matrix proteins prior to the onset of mineralization, leading to a matrix composition with reduced or no mineralizing capacity. These findings demonstrate the regulation of osteoblast differentiation and matrix mineralization by the activin A-follistatin system, providing the possibility to control bone quality as well as pathological calcifications such as atherosclerosis by using activin A, follistatin, or analogs thereof.
Eijken
Marco
M
Erasmus MC, Department Internal Medicine, 3000 CA, Rotterdam, The Netherlands.
Swagemakers
Sigrid
S
Koedam
Marijke
M
Steenbergen
Cobie
C
Derkx
Pieter
P
Uitterlinden
André G
AG
van der Spek
Peter J
PJ
Visser
Jenny A
JA
de Jong
Frank H
FH
Pols
Huibert A P
HA
van Leeuwen
Johannes P T M
JP
D028341:Activins / Q000494:pharmacology*; D000469:Alkaline Phosphatase / Q000378:metabolism; D019898:Autocrine Communication; D015415:Biomarkers / Q000378:metabolism; D002113:Calcification, Physiologic; D002114:Calcinosis / Q000517:prevention & control; D002454:Cell Differentiation; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000502:physiology*; D038681:Follistatin / Q000494:pharmacology*; D020869:Gene Expression Profiling; D006801:Humans; D007265:Inhibins / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*
D015415:Biomarkers; D038681:Follistatin; C422405:activin A; C422362:inhibin A; D028341:Activins; D007265:Inhibins; D008156:Luciferases; D000469:Alkaline Phosphatase