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The interplay of osteogenesis and hematopoiesis: expression of a constitutively active PTH/PTHrP receptor in osteogenic cells perturbs the establishment of hematopoiesis in bone and of skeletal stem cells in the bone marrow.

Kuznetsov SA, Riminucci M, Ziran N, Tsutsui TW, Corsi A, Calvi L, Kronenberg HM, Schipani E, Robey PG, Bianco P - J. Cell Biol. (2004)

Bottom Line: The transgene promoted increased bone formation within prospective marrow space, but delayed the transition from bone to bone marrow during growth, the formation of marrow cavities, and the appearance of stromal cell types such as marrow adipocytes and cells supporting hematopoiesis.This phenotype resolved spontaneously over time, leading to the establishment of marrow containing a greatly reduced number of clonogenic stromal cells.Thus, PTH/PTHrP signaling is a major regulator of the ontogeny of the bone marrow and its stromal tissue, and of the skeletal stem cell compartment.

View Article: PubMed Central - PubMed

Affiliation: Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.

ABSTRACT
The ontogeny of bone marrow and its stromal compartment, which is generated from skeletal stem/progenitor cells, was investigated in vivo and ex vivo in mice expressing constitutively active parathyroid hormone/parathyroid hormone-related peptide receptor (PTH/PTHrP; caPPR) under the control of the 2.3-kb bone-specific mouse Col1A1 promoter/enhancer. The transgene promoted increased bone formation within prospective marrow space, but delayed the transition from bone to bone marrow during growth, the formation of marrow cavities, and the appearance of stromal cell types such as marrow adipocytes and cells supporting hematopoiesis. This phenotype resolved spontaneously over time, leading to the establishment of marrow containing a greatly reduced number of clonogenic stromal cells. Proliferative osteoprogenitors, but not multipotent skeletal stem cells (mesenchymal stem cells), capable of generating a complete heterotopic bone organ upon in vivo transplantation were assayable in the bone marrow of caPPR mice. Thus, PTH/PTHrP signaling is a major regulator of the ontogeny of the bone marrow and its stromal tissue, and of the skeletal stem cell compartment.

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Histology of the bone/marrow organ and CFU-F frequency in mice at skeletal maturity. (a) Histology of the proximal metaphysis of the tibia in wt and tg mice at 4.5 mo. Hematopoietic marrow now fills the marrow cavity up to the physis in both wt and tg mice. A marked excess of trabecular bone is observed in tg mice compared with in wt mice (undecalcified MMA sections, von Kossa staining). (b) Representative primary cultures of cells established at clonal density from wt and tg mice. Note the higher number of colonies (CFU-F) in wt cultures.
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fig5: Histology of the bone/marrow organ and CFU-F frequency in mice at skeletal maturity. (a) Histology of the proximal metaphysis of the tibia in wt and tg mice at 4.5 mo. Hematopoietic marrow now fills the marrow cavity up to the physis in both wt and tg mice. A marked excess of trabecular bone is observed in tg mice compared with in wt mice (undecalcified MMA sections, von Kossa staining). (b) Representative primary cultures of cells established at clonal density from wt and tg mice. Note the higher number of colonies (CFU-F) in wt cultures.

Mentions: Because a significant alteration in postnatal development of marrow was a key phenotypic trait of tg mice, we wanted to determine whether these changes affected the composition and functional properties of the marrow stromal cell population. To this end, stromal cell strains were established in culture from wt and tg mice at 5 mo (the age when a distinct marrow cavity had formed from which stromal cells could be harvested from tg mice). The structure of the bones from which cells were derived in culture was examined by high resolution radiographic analysis. Corresponding bones of mice of the same age as those used for establishing cell cultures were subjected first to the same kind of radiographic analysis, and then to histological analysis. This procedure demonstrated a much higher amount of trabecular bone associated with the marrow of tg mice compared with that of wt mice (Fig. 5 a). No difference in the cellular composition of hematopoietic tissue was histologically apparent in tg mice.


The interplay of osteogenesis and hematopoiesis: expression of a constitutively active PTH/PTHrP receptor in osteogenic cells perturbs the establishment of hematopoiesis in bone and of skeletal stem cells in the bone marrow.

Kuznetsov SA, Riminucci M, Ziran N, Tsutsui TW, Corsi A, Calvi L, Kronenberg HM, Schipani E, Robey PG, Bianco P - J. Cell Biol. (2004)

Histology of the bone/marrow organ and CFU-F frequency in mice at skeletal maturity. (a) Histology of the proximal metaphysis of the tibia in wt and tg mice at 4.5 mo. Hematopoietic marrow now fills the marrow cavity up to the physis in both wt and tg mice. A marked excess of trabecular bone is observed in tg mice compared with in wt mice (undecalcified MMA sections, von Kossa staining). (b) Representative primary cultures of cells established at clonal density from wt and tg mice. Note the higher number of colonies (CFU-F) in wt cultures.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172616&req=5

fig5: Histology of the bone/marrow organ and CFU-F frequency in mice at skeletal maturity. (a) Histology of the proximal metaphysis of the tibia in wt and tg mice at 4.5 mo. Hematopoietic marrow now fills the marrow cavity up to the physis in both wt and tg mice. A marked excess of trabecular bone is observed in tg mice compared with in wt mice (undecalcified MMA sections, von Kossa staining). (b) Representative primary cultures of cells established at clonal density from wt and tg mice. Note the higher number of colonies (CFU-F) in wt cultures.
Mentions: Because a significant alteration in postnatal development of marrow was a key phenotypic trait of tg mice, we wanted to determine whether these changes affected the composition and functional properties of the marrow stromal cell population. To this end, stromal cell strains were established in culture from wt and tg mice at 5 mo (the age when a distinct marrow cavity had formed from which stromal cells could be harvested from tg mice). The structure of the bones from which cells were derived in culture was examined by high resolution radiographic analysis. Corresponding bones of mice of the same age as those used for establishing cell cultures were subjected first to the same kind of radiographic analysis, and then to histological analysis. This procedure demonstrated a much higher amount of trabecular bone associated with the marrow of tg mice compared with that of wt mice (Fig. 5 a). No difference in the cellular composition of hematopoietic tissue was histologically apparent in tg mice.

Bottom Line: The transgene promoted increased bone formation within prospective marrow space, but delayed the transition from bone to bone marrow during growth, the formation of marrow cavities, and the appearance of stromal cell types such as marrow adipocytes and cells supporting hematopoiesis.This phenotype resolved spontaneously over time, leading to the establishment of marrow containing a greatly reduced number of clonogenic stromal cells.Thus, PTH/PTHrP signaling is a major regulator of the ontogeny of the bone marrow and its stromal tissue, and of the skeletal stem cell compartment.

View Article: PubMed Central - PubMed

Affiliation: Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.

ABSTRACT
The ontogeny of bone marrow and its stromal compartment, which is generated from skeletal stem/progenitor cells, was investigated in vivo and ex vivo in mice expressing constitutively active parathyroid hormone/parathyroid hormone-related peptide receptor (PTH/PTHrP; caPPR) under the control of the 2.3-kb bone-specific mouse Col1A1 promoter/enhancer. The transgene promoted increased bone formation within prospective marrow space, but delayed the transition from bone to bone marrow during growth, the formation of marrow cavities, and the appearance of stromal cell types such as marrow adipocytes and cells supporting hematopoiesis. This phenotype resolved spontaneously over time, leading to the establishment of marrow containing a greatly reduced number of clonogenic stromal cells. Proliferative osteoprogenitors, but not multipotent skeletal stem cells (mesenchymal stem cells), capable of generating a complete heterotopic bone organ upon in vivo transplantation were assayable in the bone marrow of caPPR mice. Thus, PTH/PTHrP signaling is a major regulator of the ontogeny of the bone marrow and its stromal tissue, and of the skeletal stem cell compartment.

Show MeSH