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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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Impaired development of adipose (yellow) marrow in COL1-caPPR mice. Histology of the calcaneum at 2 wk and 3 mo. At 2 wk, the wt marrow cavity contains red hematopoietic marrow (a) with scattered adipocytes, and frequent multivacuolar, developing adipocytes (c and inset). In tg mice, a distinct cavity is not observed, hematopoiesis and adipocytes are absent, and an excess of bone is present (b and d). At 3 mo, hematopoiesis is no longer present, and the marrow cavity is filled with mature adipocytes in wt mice (e). No cavity is present in tg mice, and only rare adipocytes are found in narrow vascular spaces interrupting the continuity of the excess bone (f).
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fig2: Impaired development of adipose (yellow) marrow in COL1-caPPR mice. Histology of the calcaneum at 2 wk and 3 mo. At 2 wk, the wt marrow cavity contains red hematopoietic marrow (a) with scattered adipocytes, and frequent multivacuolar, developing adipocytes (c and inset). In tg mice, a distinct cavity is not observed, hematopoiesis and adipocytes are absent, and an excess of bone is present (b and d). At 3 mo, hematopoiesis is no longer present, and the marrow cavity is filled with mature adipocytes in wt mice (e). No cavity is present in tg mice, and only rare adipocytes are found in narrow vascular spaces interrupting the continuity of the excess bone (f).

Mentions: Either red (hematopoietic) or yellow (adipose) marrow occupies specific regions in the mammalian skeleton (Tavassoli and Yoffey, 1983). In mice, the entire marrow cavity of the calcaneum is occupied by yellow marrow at skeletal maturity. Histological analysis of the calcaneum at 2 wk and 3 mo revealed that a transient phase of active hematopoiesis (red marrow) precedes the establishment of yellow marrow in wt mice (Fig. 2 a). At 2 wk, the marrow cavity of the calcaneum was well defined and contained abundant hematopoietic cells and developing adipocytes, recognizable by their typical multivacuolar morphology (Fig. 2, c and inset), similar to what is observed during phases of active adipogenesis in other species. No hematopoiesis or adipogenesis was seen in 2-wk-old tg calcaneum, in which a continuous trabecular bone structure was seen instead (Fig. 2, b and d). At 3 mo, formation of a thick bony cortex and yellow marrow filling the cavity were complete in wt mice (Fig. 2 e). In contrast, a marked excess of bone filled the marrow cavity in tg calcaneum, and only rare adipocytes were scattered in the narrow vascular spaces remaining patent (Fig. 2 f).


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)

Impaired development of adipose (yellow) marrow in COL1-caPPR mice. Histology of the calcaneum at 2 wk and 3 mo. At 2 wk, the wt marrow cavity contains red hematopoietic marrow (a) with scattered adipocytes, and frequent multivacuolar, developing adipocytes (c and inset). In tg mice, a distinct cavity is not observed, hematopoiesis and adipocytes are absent, and an excess of bone is present (b and d). At 3 mo, hematopoiesis is no longer present, and the marrow cavity is filled with mature adipocytes in wt mice (e). No cavity is present in tg mice, and only rare adipocytes are found in narrow vascular spaces interrupting the continuity of the excess bone (f).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2172616&req=5

fig2: Impaired development of adipose (yellow) marrow in COL1-caPPR mice. Histology of the calcaneum at 2 wk and 3 mo. At 2 wk, the wt marrow cavity contains red hematopoietic marrow (a) with scattered adipocytes, and frequent multivacuolar, developing adipocytes (c and inset). In tg mice, a distinct cavity is not observed, hematopoiesis and adipocytes are absent, and an excess of bone is present (b and d). At 3 mo, hematopoiesis is no longer present, and the marrow cavity is filled with mature adipocytes in wt mice (e). No cavity is present in tg mice, and only rare adipocytes are found in narrow vascular spaces interrupting the continuity of the excess bone (f).
Mentions: Either red (hematopoietic) or yellow (adipose) marrow occupies specific regions in the mammalian skeleton (Tavassoli and Yoffey, 1983). In mice, the entire marrow cavity of the calcaneum is occupied by yellow marrow at skeletal maturity. Histological analysis of the calcaneum at 2 wk and 3 mo revealed that a transient phase of active hematopoiesis (red marrow) precedes the establishment of yellow marrow in wt mice (Fig. 2 a). At 2 wk, the marrow cavity of the calcaneum was well defined and contained abundant hematopoietic cells and developing adipocytes, recognizable by their typical multivacuolar morphology (Fig. 2, c and inset), similar to what is observed during phases of active adipogenesis in other species. No hematopoiesis or adipogenesis was seen in 2-wk-old tg calcaneum, in which a continuous trabecular bone structure was seen instead (Fig. 2, b and d). At 3 mo, formation of a thick bony cortex and yellow marrow filling the cavity were complete in wt mice (Fig. 2 e). In contrast, a marked excess of bone filled the marrow cavity in tg calcaneum, and only rare adipocytes were scattered in the narrow vascular spaces remaining patent (Fig. 2 f).

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