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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 the marrow cavity and hematopoietic tissue in long bones of COL1-caPPR mice. (a) High resolution radiograms of the femurs of wt and tg mice at 2 wk. Note the marked difference in length of the marrow cavity (arrows). (b) High resolution radiograms of tibiae and fibulae of wt and tg mice at 2 wk. Note the different lengths of the primary spongiosa (arrows). (c and d) Histological sections of the distal metaphysis of the femur (c) and proximal metaphysis of the tibia (d) at 2 wk. Red marrow extends to the metaphyseal end of the primary spongiosa in wt mice (arrows), but only medullary bone is present in tg mice. (e and f) High resolution contact microradiography (e) and microCT analysis (f) of tibiae at 2 wk. The excess medullary bone formed in tg mice is obvious with both techniques. MicroCT demonstrates that the normal partition between cortical bone and marrow space is lost in tg mice, and that both are replaced by a continuous plexus of cancellous bone. Sections extend from 0.5 to 2.5 mm below the physis.
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fig1: Impaired development of the marrow cavity and hematopoietic tissue in long bones of COL1-caPPR mice. (a) High resolution radiograms of the femurs of wt and tg mice at 2 wk. Note the marked difference in length of the marrow cavity (arrows). (b) High resolution radiograms of tibiae and fibulae of wt and tg mice at 2 wk. Note the different lengths of the primary spongiosa (arrows). (c and d) Histological sections of the distal metaphysis of the femur (c) and proximal metaphysis of the tibia (d) at 2 wk. Red marrow extends to the metaphyseal end of the primary spongiosa in wt mice (arrows), but only medullary bone is present in tg mice. (e and f) High resolution contact microradiography (e) and microCT analysis (f) of tibiae at 2 wk. The excess medullary bone formed in tg mice is obvious with both techniques. MicroCT demonstrates that the normal partition between cortical bone and marrow space is lost in tg mice, and that both are replaced by a continuous plexus of cancellous bone. Sections extend from 0.5 to 2.5 mm below the physis.

Mentions: At 2 wk, the marrow cavity was well formed in the femur and tibia of wild-type (wt) mice, and clearly detectable by X-ray imaging. In contrast, the marrow cavity of Col1-caPPR transgenic (tg) mice was reduced to a small mid-diaphyseal region because of a marked extension of the primary spongiosa from the metaphyses into the diaphyses (Fig. 1, a and b). Histologically, the excess bone of tg mice was composed of bone trabeculae lined by normal-appearing osteoblasts. The area between the trabeculae was occupied by fibroblastoid cells, blood vessels, and osteoclasts, but devoid of hematopoietic cells, at 2 wk. Marrow was confined to a small diaphyseal region corresponding to the radiographically detectable marrow cavity in tg mice, whereas it extended from one metaphyseal spongiosa to the other in wt long bones (Fig. 1, c and d).


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 the marrow cavity and hematopoietic tissue in long bones of COL1-caPPR mice. (a) High resolution radiograms of the femurs of wt and tg mice at 2 wk. Note the marked difference in length of the marrow cavity (arrows). (b) High resolution radiograms of tibiae and fibulae of wt and tg mice at 2 wk. Note the different lengths of the primary spongiosa (arrows). (c and d) Histological sections of the distal metaphysis of the femur (c) and proximal metaphysis of the tibia (d) at 2 wk. Red marrow extends to the metaphyseal end of the primary spongiosa in wt mice (arrows), but only medullary bone is present in tg mice. (e and f) High resolution contact microradiography (e) and microCT analysis (f) of tibiae at 2 wk. The excess medullary bone formed in tg mice is obvious with both techniques. MicroCT demonstrates that the normal partition between cortical bone and marrow space is lost in tg mice, and that both are replaced by a continuous plexus of cancellous bone. Sections extend from 0.5 to 2.5 mm below the physis.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2172616&req=5

fig1: Impaired development of the marrow cavity and hematopoietic tissue in long bones of COL1-caPPR mice. (a) High resolution radiograms of the femurs of wt and tg mice at 2 wk. Note the marked difference in length of the marrow cavity (arrows). (b) High resolution radiograms of tibiae and fibulae of wt and tg mice at 2 wk. Note the different lengths of the primary spongiosa (arrows). (c and d) Histological sections of the distal metaphysis of the femur (c) and proximal metaphysis of the tibia (d) at 2 wk. Red marrow extends to the metaphyseal end of the primary spongiosa in wt mice (arrows), but only medullary bone is present in tg mice. (e and f) High resolution contact microradiography (e) and microCT analysis (f) of tibiae at 2 wk. The excess medullary bone formed in tg mice is obvious with both techniques. MicroCT demonstrates that the normal partition between cortical bone and marrow space is lost in tg mice, and that both are replaced by a continuous plexus of cancellous bone. Sections extend from 0.5 to 2.5 mm below the physis.
Mentions: At 2 wk, the marrow cavity was well formed in the femur and tibia of wild-type (wt) mice, and clearly detectable by X-ray imaging. In contrast, the marrow cavity of Col1-caPPR transgenic (tg) mice was reduced to a small mid-diaphyseal region because of a marked extension of the primary spongiosa from the metaphyses into the diaphyses (Fig. 1, a and b). Histologically, the excess bone of tg mice was composed of bone trabeculae lined by normal-appearing osteoblasts. The area between the trabeculae was occupied by fibroblastoid cells, blood vessels, and osteoclasts, but devoid of hematopoietic cells, at 2 wk. Marrow was confined to a small diaphyseal region corresponding to the radiographically detectable marrow cavity in tg mice, whereas it extended from one metaphyseal spongiosa to the other in wt long bones (Fig. 1, c and d).

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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