Systemically administered rhBMP-2 promotes MSC activity and reverses bone and cartilage loss in osteopenic mice

被引:102
作者
Turgeman, G
Zilberman, Y
Zhou, SH
Kelly, P
Moutsatsos, IK
Kharode, YP
Borella, LE
Bex, FJ
Komm, BS
Bodine, PVN
Gazit, D
机构
[1] Hebrew Univ Jerusalem, Hadassah Fac Dent Med, Mol Pathol Lab, Jerusalem, Israel
[2] Wyeth Pharmaceut, Genet Inst, Cambridge, MA 02140 USA
[3] Wyeth Pharmaceut, Womens Hlth Res Inst, Collegeville, PA 19426 USA
关键词
osteoporosis; ovariectomy; rhBMP-2; mesenchymal stem cells; osteogenesis;
D O I
10.1002/jcb.10231
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Osteoporosis is a disease manifested in drastic bone loss resulting in osteopenia and high risk for fractures. This disease is generally divided into two subtypes. The first, post-menopausal (type 1) osteoporosis, is primarily related to estrogen deficiency. The second, senile (type II) osteoporosis, is mostly related to aging. Decreased bone formation, as well as increased bone resorption and turnover, are thought to play roles in the pathophysiology of both types of osteoporosis. In this study, we demonstrate in murine models for both type I (estrogen deficiency) and type II (senile) osteopenia/osteoporosis that reduced bone formation is related to a decrease in adult mesenchymal stem cell (AMSC) number, osteogenic activity, and proliferation. Decreased proliferation is coupled with increased apoptosis in AMSC cultures obtained from osteopenic mice. Recombinant human bone morphogenetic protein (rhBMP-2) is a highly osteoinductive protein, promoting osteogenic differentiation of AMSCs. Systemic intra-peritoneal (i.p.) injections of rhBMP-2 into osteopenic mice were able to reverse this phenotype in the bones of these animals. Moreover, this change in bone mass was coupled to an increase in AMSCs numbers, osteogenic activity, and proliferation as well as a decrease in apoptosis. Bone formation activity was increased as well. However, the magnitude of this response to rhBMP-2 varied among different stains of mice. In old osteopenic BALB/c male mice (type II osteoporosis model), rhBMP-2 systemic treatment also restored both articular and epiphyseal cartilage width to the levels seen in young mice. In summary, our study shows that AMSCs are a good target for systemically active anabolic compounds like rhBMP-2.
引用
收藏
页码:461 / 474
页数:14
相关论文
共 85 条
  • [1] Human parathyroid hormone 1-34 reverses bone loss in ovariectomized mice
    Alexander, JM
    Bab, I
    Fish, S
    Müller, R
    Uchiyama, T
    Gronowicz, G
    Nahounou, M
    Zhao, Q
    White, DW
    Chorev, M
    Gazit, D
    Rosenblatt, M
    [J]. JOURNAL OF BONE AND MINERAL RESEARCH, 2001, 16 (09) : 1665 - 1673
  • [2] Cross-talk between cAMP and p53-generated signals in induction of differentiation and apoptosis in steroidogenic granulosa cells
    Amsterdam, A
    KerenTal, I
    Aharoni, D
    [J]. STEROIDS, 1996, 61 (04) : 252 - 256
  • [3] Apoptosis in steroidogenic cells: Structure-function analysis
    Amsterdam, A
    Dantes, A
    Selvaraj, N
    Aharoni, D
    [J]. STEROIDS, 1997, 62 (01) : 207 - 211
  • [4] BAIN SD, 1993, J BONE MINER RES, V8, P435
  • [5] Bergman RJ, 1996, J BONE MINER RES, V11, P568
  • [6] IMMUNOLOCALIZATION AND EXPRESSION OF BONE MORPHOGENETIC PROTEIN-2 AND PROTEIN-4 IN FRACTURE-HEALING
    BOSTROM, MPG
    LANE, JM
    BERBERIAN, WS
    MISSRI, AAE
    TOMIN, E
    WEILAND, A
    DOTY, SB
    GLASER, D
    ROSEN, VM
    [J]. JOURNAL OF ORTHOPAEDIC RESEARCH, 1995, 13 (03) : 357 - 367
  • [7] Osteoinductive growth factors in preclinical fracture and long bone defects models
    Bostrom, MPG
    Saleh, KJ
    Einhorn, TA
    [J]. ORTHOPEDIC CLINICS OF NORTH AMERICA, 1999, 30 (04) : 647 - +
  • [8] Expression of bone morphogenetic proteins in fracture healing
    Bostrom, MPG
    [J]. CLINICAL ORTHOPAEDICS AND RELATED RESEARCH, 1998, (355) : S116 - S123
  • [9] Bruder SP, 1997, J CELL BIOCHEM, V64, P278, DOI 10.1002/(SICI)1097-4644(199702)64:2<278::AID-JCB11>3.0.CO
  • [10] 2-F