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Heterozygous inactivation of Gnas in adipose‐derived mesenchymal progenitor cells enhances osteoblast differentiation and promotes heterotopic ossification
Author(s) -
Pignolo Robert J,
Xu Meiqi,
Russell Elizabeth,
Richardson Alec,
Kaplan Josef,
Billings Paul C,
Kaplan Frederick S,
Shore Eileen M
Publication year - 2011
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.481
Subject(s) - gnas complex locus , mesenchymal stem cell , heterotopic ossification , progenitor cell , osteoblast , adipose tissue , progenitor , microbiology and biotechnology , ossification , cancer research , chemistry , endocrinology , biology , stem cell , anatomy , genetics , gene , in vitro
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 s α) of adenylyl cyclase, and the extralong form of G s α, 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 s α in bone‐lining cells and to G s α and XLαs in osteocytes. By contrast, the GNAS proteins G s α, 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 s α‐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. © 2011 American Society for Bone and Mineral Research