Heterozygous inactivation of Gnas in adipose-derived mesenchymal progenitor cells enhances osteoblast differentiation and promotes heterotopic ossification

Robert Pignolo, Meiqi Xu, Elizabeth Russell, Alec Richardson, Josef Kaplan, Paul C. Billings, Frederick S. Kaplan, Eileen M. Shore

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Human genetic disorders sharing the common feature of subcutaneous heterotopic ossification (HO) are caused by heterozygous inactivating mutations in GNAS, a gene encoding multiple transcripts including two stimulatory G proteins, the α subunit of the stimulatory G protein (G sα) of adenylyl cyclase, and the extralong form of G sα, XLαs. In one such disorder, progressive osseous heteroplasia (POH), bone formation initiates within subcutaneous fat before progressing to deeper tissues, suggesting that osteogenesis may involve abnormal differentiation of mesenchymal precursors that are present in adipose tissues. We determined by immunohistochemical analysis that GNAS protein expression is limited to G sα in bone-lining cells and to G sα and XLαs in osteocytes. By contrast, the GNAS proteins G sα, XLαs, and NESP55 are detected in adipocytes and in adipose stroma. Although Gnas transcripts, as assessed by quantitative RT-PCR, show no significant changes on osteoblast differentiation of bone-derived precursor cells, the abundance of these transcripts is enhanced by osteoblast differentiation of adipose-derived mesenchymal progenitors. Using a mouse knockout model, we determined that heterozygous inactivation of Gnas (by disruption of the G sα-specific exon 1) abrogates upregulation of multiple Gnas transcripts that normally occurs with osteoblast differentiation in wild-type adipose stromal cells. These transcriptional changes in Gnas +/- mice are accompanied by accelerated osteoblast differentiation of adipose stromal cells in vitro. In vivo, altered osteoblast differentiation in Gnas +/- mice manifests as subcutaneous HO by an intramembranous process. Taken together, these data suggest that Gnas is a key regulator of fate decisions in adipose-derived mesenchymal progenitor cells, specifically those which are involved in bone formation.

Original languageEnglish (US)
Pages (from-to)2647-2655
Number of pages9
JournalJournal of Bone and Mineral Research
Volume26
Issue number11
DOIs
StatePublished - Nov 1 2011
Externally publishedYes

Fingerprint

Heterotopic Ossification
Osteoblasts
Mesenchymal Stromal Cells
Osteogenesis
Stromal Cells
GTP-Binding Proteins
Bone and Bones
Osteocytes
Gastrin-Secreting Cells
Inborn Genetic Diseases
Subcutaneous Fat
Protein Subunits
Medical Genetics
Adenylyl Cyclases
Adipocytes
Knockout Mice
Adipose Tissue
Exons
Proteins
Up-Regulation

Keywords

  • Albright hereditary osteodystrophy (AHO)
  • GNAS/Gnas
  • Heterotopic ossification
  • Osteoblast differentiation
  • Osteoma cutis (OC)
  • Progressive osseous heteroplasia (POH)
  • Pseudohypoparathyroidism (PHP)

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

Heterozygous inactivation of Gnas in adipose-derived mesenchymal progenitor cells enhances osteoblast differentiation and promotes heterotopic ossification. / Pignolo, Robert; Xu, Meiqi; Russell, Elizabeth; Richardson, Alec; Kaplan, Josef; Billings, Paul C.; Kaplan, Frederick S.; Shore, Eileen M.

In: Journal of Bone and Mineral Research, Vol. 26, No. 11, 01.11.2011, p. 2647-2655.

Research output: Contribution to journalArticle

Pignolo, Robert ; Xu, Meiqi ; Russell, Elizabeth ; Richardson, Alec ; Kaplan, Josef ; Billings, Paul C. ; Kaplan, Frederick S. ; Shore, Eileen M. / Heterozygous inactivation of Gnas in adipose-derived mesenchymal progenitor cells enhances osteoblast differentiation and promotes heterotopic ossification. In: Journal of Bone and Mineral Research. 2011 ; Vol. 26, No. 11. pp. 2647-2655.
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AU - Kaplan, Josef

AU - Billings, Paul C.

AU - Kaplan, Frederick S.

AU - Shore, Eileen M.

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