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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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Gross, radiographic, and histological analysis of subcutaneous transplants of stromal strains in conjunction with collagen sponges. Gross appearance of the transplants generated by wt (a and e) and tg (c and g) strains harvested at 42 (a and c) and 56 d (e and g). Hematopoiesis gives a red color to wt transplants (a and e), whereas the collagen sponge remains pale gray in spite of vascularization (well apparent in c) in tg transplants (c and g). High resolution radiograms of the same structures for wt (b and f) and tg (d and h) transplants. Bone formation is readily detected in wt transplants (b and f), and even a distinct bony cortex is easily resolved in the ectopic ossicles. No bone was formed by tg cells (d and h). (i and j) Nondecalcified sections stained with Goldner's trichrome stain. (k–n) Paraffin sections stained with H&E. (i–n) Examination of wt transplants at 28 (i), 42 (k), and 56 d (m) revealed the progressive formation of a complete heterotopic ossicle, including a bony cortex and a medullary cavity with trabecular bone (*), and the establishment of a complete hematopoietic marrow. Fully mature adipocytes (#) are well apparent by day 42. Neither bone nor a hematopoietic marrow was present at any time point in tg transplants (j, l, and n).
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fig8: Gross, radiographic, and histological analysis of subcutaneous transplants of stromal strains in conjunction with collagen sponges. Gross appearance of the transplants generated by wt (a and e) and tg (c and g) strains harvested at 42 (a and c) and 56 d (e and g). Hematopoiesis gives a red color to wt transplants (a and e), whereas the collagen sponge remains pale gray in spite of vascularization (well apparent in c) in tg transplants (c and g). High resolution radiograms of the same structures for wt (b and f) and tg (d and h) transplants. Bone formation is readily detected in wt transplants (b and f), and even a distinct bony cortex is easily resolved in the ectopic ossicles. No bone was formed by tg cells (d and h). (i and j) Nondecalcified sections stained with Goldner's trichrome stain. (k–n) Paraffin sections stained with H&E. (i–n) Examination of wt transplants at 28 (i), 42 (k), and 56 d (m) revealed the progressive formation of a complete heterotopic ossicle, including a bony cortex and a medullary cavity with trabecular bone (*), and the establishment of a complete hematopoietic marrow. Fully mature adipocytes (#) are well apparent by day 42. Neither bone nor a hematopoietic marrow was present at any time point in tg transplants (j, l, and n).

Mentions: Under nonosteoconductive conditions (transplants in collagen sponges), in 12 out of 12 transplants, wt strains formed complete ossicles, composed of a shell of cortical bone and a marrow cavity with bone trabeculae; complete hematopoiesis (granulo-, erythro-, and megakaryopoiesis); and adipocytes (Fig. 8). Early developmental phases of bone and marrow formation (deposition of bone by osteoblasts, adipogenesis, establishment of a sinusoidal vascular bed, and removal of the collagen carrier) were well apparent in wt transplants harvested at 28 d, and formation of a fully structured ossicle was complete at 56 d. In contrast, in spite of the high number of CFU-Fs transplanted, tg strains consistently failed to establish a heterotopic bone organ upon transplantation (no ossicle formation was observed in 12 out of 12 transplants of tg strains; Fig. 8).


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)

Gross, radiographic, and histological analysis of subcutaneous transplants of stromal strains in conjunction with collagen sponges. Gross appearance of the transplants generated by wt (a and e) and tg (c and g) strains harvested at 42 (a and c) and 56 d (e and g). Hematopoiesis gives a red color to wt transplants (a and e), whereas the collagen sponge remains pale gray in spite of vascularization (well apparent in c) in tg transplants (c and g). High resolution radiograms of the same structures for wt (b and f) and tg (d and h) transplants. Bone formation is readily detected in wt transplants (b and f), and even a distinct bony cortex is easily resolved in the ectopic ossicles. No bone was formed by tg cells (d and h). (i and j) Nondecalcified sections stained with Goldner's trichrome stain. (k–n) Paraffin sections stained with H&E. (i–n) Examination of wt transplants at 28 (i), 42 (k), and 56 d (m) revealed the progressive formation of a complete heterotopic ossicle, including a bony cortex and a medullary cavity with trabecular bone (*), and the establishment of a complete hematopoietic marrow. Fully mature adipocytes (#) are well apparent by day 42. Neither bone nor a hematopoietic marrow was present at any time point in tg transplants (j, l, and n).
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Related In: Results  -  Collection

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fig8: Gross, radiographic, and histological analysis of subcutaneous transplants of stromal strains in conjunction with collagen sponges. Gross appearance of the transplants generated by wt (a and e) and tg (c and g) strains harvested at 42 (a and c) and 56 d (e and g). Hematopoiesis gives a red color to wt transplants (a and e), whereas the collagen sponge remains pale gray in spite of vascularization (well apparent in c) in tg transplants (c and g). High resolution radiograms of the same structures for wt (b and f) and tg (d and h) transplants. Bone formation is readily detected in wt transplants (b and f), and even a distinct bony cortex is easily resolved in the ectopic ossicles. No bone was formed by tg cells (d and h). (i and j) Nondecalcified sections stained with Goldner's trichrome stain. (k–n) Paraffin sections stained with H&E. (i–n) Examination of wt transplants at 28 (i), 42 (k), and 56 d (m) revealed the progressive formation of a complete heterotopic ossicle, including a bony cortex and a medullary cavity with trabecular bone (*), and the establishment of a complete hematopoietic marrow. Fully mature adipocytes (#) are well apparent by day 42. Neither bone nor a hematopoietic marrow was present at any time point in tg transplants (j, l, and n).
Mentions: Under nonosteoconductive conditions (transplants in collagen sponges), in 12 out of 12 transplants, wt strains formed complete ossicles, composed of a shell of cortical bone and a marrow cavity with bone trabeculae; complete hematopoiesis (granulo-, erythro-, and megakaryopoiesis); and adipocytes (Fig. 8). Early developmental phases of bone and marrow formation (deposition of bone by osteoblasts, adipogenesis, establishment of a sinusoidal vascular bed, and removal of the collagen carrier) were well apparent in wt transplants harvested at 28 d, and formation of a fully structured ossicle was complete at 56 d. In contrast, in spite of the high number of CFU-Fs transplanted, tg strains consistently failed to establish a heterotopic bone organ upon transplantation (no ossicle formation was observed in 12 out of 12 transplants of tg strains; Fig. 8).

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