Insulin-like growth factor-binding protein-5 inhibits osteoblast differentiation and skeletal growth by blocking insulin-like growth factor actions

Aditi Mukherjee, Peter Rotwein

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Signaling through the IGF-I receptor by locally synthesized IGF-I or IGF-II is critical for normal skeletal development and for bone remodeling and repair throughout the lifespan. In most tissues, IGF actions are modulated by IGF-binding proteins (IGFBPs). IGFBP-5 is the most abundant IGFBP in bone, and previous studies have suggested that it may either enhance or inhibit osteoblast differentiation in culture and may facilitate or block bone growth in vivo. To resolve these contradictory observations and discern the mechanisms of action of IGFBP-5 in bone, we studied its effects in differentiating osteoblasts and in primary bone cultures. Purified wild-type (WT) mouse IGFBP-5 or a recombinant adenovirus expressing IGFBP-5WT each prevented osteogenic differentiation induced by the cytokine bone morphogenetic protein (BMP)-2 at its earliest stages without interfering with BMP-mediated signaling, whereas an analog with reduced IGF binding (N domain mutant) was ineffective. When added at later phases of bone cell maturation, IGFBP-5WT but not IGFBP-5 N blocked mineralization, prevented longitudinal growth of mouse metatarsal bones in short-term primary culture, and inhibited their endochondral ossification. Because an IGF-I variant (R3IGF-I) with diminished affinity for IGFBPs promoted full osteogenic differentiation in the presence of IGFBP-5WT, our results show that IGFBP-5 interferes with IGF action in osteoblasts and provides a framework for discerning mechanisms of collaboration between signal transduction pathways activated by BMPs and IGFs in bone.

Original languageEnglish (US)
Pages (from-to)1238-1250
Number of pages13
JournalMolecular Endocrinology
Volume22
Issue number5
DOIs
StatePublished - May 2008

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Insulin-Like Growth Factor Binding Protein 5
Insulin-Like Growth Factor Binding Proteins
Somatomedins
Osteoblasts
Bone and Bones
Growth
Insulin-Like Growth Factor I
Bone Morphogenetic Protein 2
IGF Type 1 Receptor
Bone Morphogenetic Proteins
Insulin-Like Growth Factor II
Metatarsal Bones
Bone Remodeling
Bone Development
Adenoviridae
Osteogenesis
Signal Transduction
Cytokines

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Cite this

Insulin-like growth factor-binding protein-5 inhibits osteoblast differentiation and skeletal growth by blocking insulin-like growth factor actions. / Mukherjee, Aditi; Rotwein, Peter.

In: Molecular Endocrinology, Vol. 22, No. 5, 05.2008, p. 1238-1250.

Research output: Contribution to journalArticle

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