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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
2 Dipartimento di Medicina Sperimentale, Università dell'Aquila, 67010 L'Aquila, Italy
3 Parco Scientifico Biomedico San Raffaele, 00161 Rome, Italy
4 Dipartimento di Medicina Sperimentale e Patologia, Università "La Sapienza," 3 00161 Rome, Italy
5 Endocrine Unit, Massachusetts General Hospital, and Harvard Medical School, Boston, MA 02114
Correspondence to Pamela Gehron Robey: probey{at}dir.nidcr.nih.gov; or Paolo Bianco: p.bianco{at}flashnet.it
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.
N. Ziran's present address is Dept. of Orthopaedics, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642.
T.W. Tsutsui's present address is Dept. of Pharmacology, The Nippon Dental University, School of Dentistry at Tokyo, Tokyo 102-8159, Japan.
L. Calvi's present address is Endocrine/Metabolism Unit, Strong Memorial Hospital, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642.
Abbreviations used in this paper: caPPR, constitutively active PPR; CFE, colony-forming efficiency; CFU-F, colony-forming unit–fibroblast; FD, fibrous dysplasia; H&E, hematoxylin and eosin; HA/TCP, hydroxyapatite/tricalcium phosphate; HSC, hematopoietic stem cell; microCT, microcomputerized tomography; MMA, methyl methacrylate; OP, osteoprogenitor; PPR, PTH/PTHrP receptor; PTH/PTHrP, parathyroid hormone/parathyroid hormone–related peptide; SSC, skeletal stem cell; tg, transgenic; wt, wild-type.
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