Skeletal overexpression of gremlin impairs bone formation and causes osteopenia

Elisabetta Gazzerro, Renata C. Pereira, Vanda Jorgetti, Sarah Olson, Aris N. Economides, Ernesto Canalis

Research output: Contribution to journalArticle

Abstract

Skeletal cells synthesize bone morphogenetic proteins (BMPs) and BMP antagonists. Gremlin, a BMP antagonist, is expressed in osteoblasts and opposes BMP effects on osteoblastic differentiation and function in vitro. However, its effects in vivo are not known. To investigate the actions of gremlin on bone remodeling in vivo, we generated transgenic mice overexpressing gremlin under the control of the osteocalcin promoter. Gremlin transgenics exhibited bone fractures and reduced bone mineral density by 20-30%, compared with controls. Static and dynamic histomorphometry of femurs revealed that gremlin overexpression caused reduced trabecular bone volume and the appearance of woven bone. Polarized light microscopy revealed disorganized collagen bundles at the endosteal cortical surface. Gremlin transgenic mice displayed a 70% decrease in the number of osteoblasts/trabecular area and reduced mineral apposition and bone formation rates. In vivo bromodeoxyuridine labeling and marrow stromal cell cultures demonstrated an inhibitory effect of gremlin on osteoblastic cell replication, but no change on apoptosis was detected. Marrow stromal cells from gremlin transgenics displayed a reduced response to BMP on phosphorylated mothers against decapentaplegic 1/5/8 phosphorylation and reduced free cytosolic β-catenin levels. In conclusion, transgenic mice overexpressing gremlin in the bone microenvironment have decreased osteoblast number and function leading to osteopenia and spontaneous fractures.

Original languageEnglish
Pages (from-to)655-665
Number of pages11
JournalEndocrinology
Volume146
Issue number2
DOIs
Publication statusPublished - Feb 2005

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Bone Morphogenetic Proteins
Metabolic Bone Diseases
Osteogenesis
Osteoblasts
Transgenic Mice
Stromal Cells
Bone Marrow
Polarization Microscopy
Bone and Bones
Catenins
Spontaneous Fractures
Bone Remodeling
Osteocalcin
Bone Fractures
Bromodeoxyuridine
Bone Density
Femur
Minerals
Collagen
Cell Culture Techniques

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Gazzerro, E., Pereira, R. C., Jorgetti, V., Olson, S., Economides, A. N., & Canalis, E. (2005). Skeletal overexpression of gremlin impairs bone formation and causes osteopenia. Endocrinology, 146(2), 655-665. https://doi.org/10.1210/en.2004-0766

Skeletal overexpression of gremlin impairs bone formation and causes osteopenia. / Gazzerro, Elisabetta; Pereira, Renata C.; Jorgetti, Vanda; Olson, Sarah; Economides, Aris N.; Canalis, Ernesto.

In: Endocrinology, Vol. 146, No. 2, 02.2005, p. 655-665.

Research output: Contribution to journalArticle

Gazzerro, E, Pereira, RC, Jorgetti, V, Olson, S, Economides, AN & Canalis, E 2005, 'Skeletal overexpression of gremlin impairs bone formation and causes osteopenia', Endocrinology, vol. 146, no. 2, pp. 655-665. https://doi.org/10.1210/en.2004-0766
Gazzerro E, Pereira RC, Jorgetti V, Olson S, Economides AN, Canalis E. Skeletal overexpression of gremlin impairs bone formation and causes osteopenia. Endocrinology. 2005 Feb;146(2):655-665. https://doi.org/10.1210/en.2004-0766
Gazzerro, Elisabetta ; Pereira, Renata C. ; Jorgetti, Vanda ; Olson, Sarah ; Economides, Aris N. ; Canalis, Ernesto. / Skeletal overexpression of gremlin impairs bone formation and causes osteopenia. In: Endocrinology. 2005 ; Vol. 146, No. 2. pp. 655-665.
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