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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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Osteogenic potential of stromal strains. (a) Histology of ectopic ossicles formed subcutaneously in immunocompromised mice by strains derived from wt and tg mice transplanted with an osteoconductive carrier (HA/TCP particles; HA). Formation of bone (b) and marrow (bm) is obvious in transplants of wt cells at 28, 42, and 56 d. Adipocytes in the hematopoietic marrow are evident at 42 and 56 d. Formation of bone, but not of red marrow, is obvious in transplants of tg cells at 28, 42, and 56 d. Adipocytes are not formed, and only fibrous tissue (ft) fills the spaces between bone surfaces. (b) Histomorphometric assessment of the amount of bone (bone volume/total volume; BV/TV %) formed in ectopic ossicles did not reveal differences between wt and tg strains at any time point. A similar increase in the amount of bone was observed at 56 d compared with earlier time points in wt and tg transplants. Error bars indicate SD of the mean.
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fig7: Osteogenic potential of stromal strains. (a) Histology of ectopic ossicles formed subcutaneously in immunocompromised mice by strains derived from wt and tg mice transplanted with an osteoconductive carrier (HA/TCP particles; HA). Formation of bone (b) and marrow (bm) is obvious in transplants of wt cells at 28, 42, and 56 d. Adipocytes in the hematopoietic marrow are evident at 42 and 56 d. Formation of bone, but not of red marrow, is obvious in transplants of tg cells at 28, 42, and 56 d. Adipocytes are not formed, and only fibrous tissue (ft) fills the spaces between bone surfaces. (b) Histomorphometric assessment of the amount of bone (bone volume/total volume; BV/TV %) formed in ectopic ossicles did not reveal differences between wt and tg strains at any time point. A similar increase in the amount of bone was observed at 56 d compared with earlier time points in wt and tg transplants. Error bars indicate SD of the mean.

Mentions: The ability of wt and tg cell strains to generate a complete heterotopic bone organ and establish a hematopoietic microenvironment was tested with two different in vivo transplantation assays. We performed transplants using either a mineral phase (hydroxyapatite/tricalcium phosphate [HA/TCP]) or a nonmineralized, collagenous carrier. The two carriers differ with respect to their osteoconductive properties. Whereas HA/TCP facilitates bone deposition by cells competent for bone formation by providing a preexisting mineralized scaffold (Damien and Parsons, 1991), collagen, per se, does not. In 12 out of 12 transplants made with wt strains and HA/TCP, bone, hematopoietic tissue, and adipocytes were evident at all time points. In contrast, bone and fibrous tissue, but neither hematopoietic tissue nor marrow adipocytes, were formed in 12 out of 12 transplants of tg strains with HA/TCP (Fig. 7 a). The amount of bone formed in the transplants was assessed by histomorphometry and was found to be essentially the same for wt and tg strains at all time points (Fig. 7 b).


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)

Osteogenic potential of stromal strains. (a) Histology of ectopic ossicles formed subcutaneously in immunocompromised mice by strains derived from wt and tg mice transplanted with an osteoconductive carrier (HA/TCP particles; HA). Formation of bone (b) and marrow (bm) is obvious in transplants of wt cells at 28, 42, and 56 d. Adipocytes in the hematopoietic marrow are evident at 42 and 56 d. Formation of bone, but not of red marrow, is obvious in transplants of tg cells at 28, 42, and 56 d. Adipocytes are not formed, and only fibrous tissue (ft) fills the spaces between bone surfaces. (b) Histomorphometric assessment of the amount of bone (bone volume/total volume; BV/TV %) formed in ectopic ossicles did not reveal differences between wt and tg strains at any time point. A similar increase in the amount of bone was observed at 56 d compared with earlier time points in wt and tg transplants. Error bars indicate SD of the mean.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2172616&req=5

fig7: Osteogenic potential of stromal strains. (a) Histology of ectopic ossicles formed subcutaneously in immunocompromised mice by strains derived from wt and tg mice transplanted with an osteoconductive carrier (HA/TCP particles; HA). Formation of bone (b) and marrow (bm) is obvious in transplants of wt cells at 28, 42, and 56 d. Adipocytes in the hematopoietic marrow are evident at 42 and 56 d. Formation of bone, but not of red marrow, is obvious in transplants of tg cells at 28, 42, and 56 d. Adipocytes are not formed, and only fibrous tissue (ft) fills the spaces between bone surfaces. (b) Histomorphometric assessment of the amount of bone (bone volume/total volume; BV/TV %) formed in ectopic ossicles did not reveal differences between wt and tg strains at any time point. A similar increase in the amount of bone was observed at 56 d compared with earlier time points in wt and tg transplants. Error bars indicate SD of the mean.
Mentions: The ability of wt and tg cell strains to generate a complete heterotopic bone organ and establish a hematopoietic microenvironment was tested with two different in vivo transplantation assays. We performed transplants using either a mineral phase (hydroxyapatite/tricalcium phosphate [HA/TCP]) or a nonmineralized, collagenous carrier. The two carriers differ with respect to their osteoconductive properties. Whereas HA/TCP facilitates bone deposition by cells competent for bone formation by providing a preexisting mineralized scaffold (Damien and Parsons, 1991), collagen, per se, does not. In 12 out of 12 transplants made with wt strains and HA/TCP, bone, hematopoietic tissue, and adipocytes were evident at all time points. In contrast, bone and fibrous tissue, but neither hematopoietic tissue nor marrow adipocytes, were formed in 12 out of 12 transplants of tg strains with HA/TCP (Fig. 7 a). The amount of bone formed in the transplants was assessed by histomorphometry and was found to be essentially the same for wt and tg strains at all time points (Fig. 7 b).

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