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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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Transient fibrous dysplastic phase in bone and marrow of Col1-PPR mice. (a and b) Transmitted light views of standard H&E-stained sections of the proximal metaphysis of the tibia at 2 wk and 3 mo. The medullary bone is lined by typical cuboidal osteoblasts (ob) at 2 wk (a), and, although excessive, it is otherwise histologically normal. In contrast, morphologically typical osteoblasts cannot be recognized, and only spindle-shaped cells (sc) fill the spaces between trabeculae at 3 mo (b). The orientation of trabeculae is more haphazard, giving the tissue a dysplastic appearance. (c and d) Fluorescence microscopy images of the same sections. No cement lines (marks of bone remodeling events) are seen at 2 wk (c), which is consistent with the primary nature of the medullary bone. A complex pattern of cement lines (which remain nonfluorescent in H&E-stained sections) is seen at 3 mo (d, arrows), testifying to the occurrence of multiple remodeling cycles.
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fig4: Transient fibrous dysplastic phase in bone and marrow of Col1-PPR mice. (a and b) Transmitted light views of standard H&E-stained sections of the proximal metaphysis of the tibia at 2 wk and 3 mo. The medullary bone is lined by typical cuboidal osteoblasts (ob) at 2 wk (a), and, although excessive, it is otherwise histologically normal. In contrast, morphologically typical osteoblasts cannot be recognized, and only spindle-shaped cells (sc) fill the spaces between trabeculae at 3 mo (b). The orientation of trabeculae is more haphazard, giving the tissue a dysplastic appearance. (c and d) Fluorescence microscopy images of the same sections. No cement lines (marks of bone remodeling events) are seen at 2 wk (c), which is consistent with the primary nature of the medullary bone. A complex pattern of cement lines (which remain nonfluorescent in H&E-stained sections) is seen at 3 mo (d, arrows), testifying to the occurrence of multiple remodeling cycles.

Mentions: Occurrence of multiple remodeling cycles in the extended primary spongiosa (“medullary bone”) originally formed in lieu of marrow space in tg mice was confirmed by histological studies (Fig. 4). Between 2 wk and 5 mo, fluorescence microscopy of hematoxylin and eosin (H&E)–stained sections visualized complex arrays of cement/reversal lines (each marking an individual remodeling cycle) within the medullary trabeculae of tg mice (Fig. 4 d). At the same time, a marked change in the morphology of cells residing on trabecular surfaces and within intertrabecular areas was observed. Although osteoblasts of normal morphology lined the surface of primary medullary bone trabeculae at 2 wk (Fig. 4 a), cells associated with medullary bone at 3 mo were uniformly spindle shaped and fibroblastic in habit (Fig. 4 b). Together, cell morphology, accumulation of fibrous tissue, and abnormal bone structure compounded a dysplastic pattern reminiscent of human fibrous dysplasia (FD; Riminucci et al., 1997, 1999). The relative length of the region occupied by dysplastic bone and fibrous tissue decreased over time and was limited to a narrow metaphyseal region at 4 mo. At 5 mo, a hematopoietic marrow extended to the physis proper. However, throughout the metaphysis, an overt excess of trabecular bone was demonstrated histologically in tg mice, matching the radiographic analysis.


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)

Transient fibrous dysplastic phase in bone and marrow of Col1-PPR mice. (a and b) Transmitted light views of standard H&E-stained sections of the proximal metaphysis of the tibia at 2 wk and 3 mo. The medullary bone is lined by typical cuboidal osteoblasts (ob) at 2 wk (a), and, although excessive, it is otherwise histologically normal. In contrast, morphologically typical osteoblasts cannot be recognized, and only spindle-shaped cells (sc) fill the spaces between trabeculae at 3 mo (b). The orientation of trabeculae is more haphazard, giving the tissue a dysplastic appearance. (c and d) Fluorescence microscopy images of the same sections. No cement lines (marks of bone remodeling events) are seen at 2 wk (c), which is consistent with the primary nature of the medullary bone. A complex pattern of cement lines (which remain nonfluorescent in H&E-stained sections) is seen at 3 mo (d, arrows), testifying to the occurrence of multiple remodeling cycles.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2172616&req=5

fig4: Transient fibrous dysplastic phase in bone and marrow of Col1-PPR mice. (a and b) Transmitted light views of standard H&E-stained sections of the proximal metaphysis of the tibia at 2 wk and 3 mo. The medullary bone is lined by typical cuboidal osteoblasts (ob) at 2 wk (a), and, although excessive, it is otherwise histologically normal. In contrast, morphologically typical osteoblasts cannot be recognized, and only spindle-shaped cells (sc) fill the spaces between trabeculae at 3 mo (b). The orientation of trabeculae is more haphazard, giving the tissue a dysplastic appearance. (c and d) Fluorescence microscopy images of the same sections. No cement lines (marks of bone remodeling events) are seen at 2 wk (c), which is consistent with the primary nature of the medullary bone. A complex pattern of cement lines (which remain nonfluorescent in H&E-stained sections) is seen at 3 mo (d, arrows), testifying to the occurrence of multiple remodeling cycles.
Mentions: Occurrence of multiple remodeling cycles in the extended primary spongiosa (“medullary bone”) originally formed in lieu of marrow space in tg mice was confirmed by histological studies (Fig. 4). Between 2 wk and 5 mo, fluorescence microscopy of hematoxylin and eosin (H&E)–stained sections visualized complex arrays of cement/reversal lines (each marking an individual remodeling cycle) within the medullary trabeculae of tg mice (Fig. 4 d). At the same time, a marked change in the morphology of cells residing on trabecular surfaces and within intertrabecular areas was observed. Although osteoblasts of normal morphology lined the surface of primary medullary bone trabeculae at 2 wk (Fig. 4 a), cells associated with medullary bone at 3 mo were uniformly spindle shaped and fibroblastic in habit (Fig. 4 b). Together, cell morphology, accumulation of fibrous tissue, and abnormal bone structure compounded a dysplastic pattern reminiscent of human fibrous dysplasia (FD; Riminucci et al., 1997, 1999). The relative length of the region occupied by dysplastic bone and fibrous tissue decreased over time and was limited to a narrow metaphyseal region at 4 mo. At 5 mo, a hematopoietic marrow extended to the physis proper. However, throughout the metaphysis, an overt excess of trabecular bone was demonstrated histologically in tg mice, matching the radiographic analysis.

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
Related in: MedlinePlus