Dysregulated in vitro hematopoiesis, radiosensitivity, proliferation, and osteoblastogenesis with marrow from SAMP6 mice.
The senescence accelerated-prone mouse variant 6 (SAMP6) shows normal growth followed by rapid aging, development of osteopenia, and shortened lifespan, compared with control R1 mice. Because oxidative stress is a fundamental mechanism of tissue aging, we tested whether cellular parameters that are associated with oxidative stress are impaired with marrow from SAMP6 mice. We compared in vitro hematopoiesis, irradiation sensitivity, proliferative potential, and osteoblastogenesis with marrow cells from SAMP6 and R1 mice. Marrow cells from SAMP6 mice showed shortened in vitro hematopoiesis; their stromal cells showed greater radiation sensitivity and decreased proliferation. Consistent with those properties, there was constitutive upregulation of transforming growth factor-β(1), an inhibitor of hematopoiesis, and of cell cycle inhibitory genes, p16(INK4A) and p19(ARF). Paradoxically, there was constitutive expression of osteoblast genes in stromal cells from SAMP6 mice, but in vitro matrix mineralization was impaired. These studies and data included in other reports indicate that impaired proliferation of osteoblast progenitors in SAMP6 marrow may be a major factor contributing to accelerated loss of bone mass. In sum, marrow from SAMP6 mice had diminished capacity for long-term hematopoiesis, increased radiosensitivity, and reduced proliferative capacity.
Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Regina P
RP
O'Sullivan
Joel S
JS
Greenberger
Julie
J
Goff
Shaonan
S
Cao
Kiera A
KA
Kingston
Shuanhu
S
Zhou
Tracy
T
Dixon
Frank D
FD
Houghton
Michael W
MW
Epperly
Hong
H
Wang
Julie
J
Glowacki
D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology*; D002478:Cells, Cultured; D006410:Hematopoiesis; D066298:In Vitro Techniques; D051379:Mice; D010006:Osteoblasts / Q000166:cytology*; D018384:Oxidative Stress; D011836:Radiation Tolerance; D020133:Reverse Transcriptase Polymerase Chain Reaction