Increased bone formation by intermittent parathyroid hormone administration is due to the stimulation of proliferation and differentiation of osteoprogenitor cells in bone marrow

Nishida, Saburo; Yamaguchi, Akira; Tanizawa, Tatsuhiko; Endo, Naoto; Mashiba, Tasuku; Uchiyama, Yasushi; Suda, Takafumi; Yoshiki, Shusaku; Takahashi, Hideaki

doi:10.1016/8756-3282(94)90322-0

Cited by 230 publications

(134 citation statements)

References 24 publications

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“…PTH has also been shown to stimulate production of prostaglandins from rat osteogenic cells resulting in stimulated bone formation (27). Furthermore, PTH may stimulate bone marrow osteoprogenitor cells to proliferate, migrate and differentiate into osteoblasts if the bone tissue is loaded normally (28,29). This process may be the one that enables formation of new cancellous bone in the distal femoral diaphysis of the old rats in the present study.…”

Section: Discussionmentioning

confidence: 66%

Parathyroid hormone induces formation of new cancellous bone with substantial mechanical strength at a site where it had disappeared in old rats

Oxlund¹,

Dalstra²,

Ejersted³

et al. 2002

European Journal of Endocrinology

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Objective: The present study addresses the question -can PTH induce formation of trabeculae in areas where cancellous bone has disappeared? Two-year-old male rats were chosen, because in this aged animal model the distal femurs have almost no cancellous bone, and the marrow cavity has reached a substantial dimension. Design: The rats were injected for 56 days with either PTH(1-34), 15 nmol/kg/day (62.5 mg/kg/day), or vehicle. Methods: Transverse specimens, 2-mm high, were cut from the distal femoral metaphysis. Marrow cavity diameters and cancellous bone trabeculae were analysed by a micro-computerized tomography scanner. The cancellous bone within the cortical and endocortical rim of each specimen was submitted to a biomechanical compression test. Furthermore, the cancellous bone was studied by dynamic tetracycline labelling and histomorphometry. Results: In the vehicle-injected group the trabecular bone volume was 0% (0 -1.4), median (range). All PTH-injected rats had trabeculae in the distal metaphysis and the trabecular bone volume (6.7% (2.3 -12.0)) was markedly increased ðP , 0:003Þ: The median trabecular thickness was increased ðP , 0:003Þ in the PTH-injected rats (118 mm (104-125)) compared with the vehicle group (0 mm (0 -71)). The compressive stress was increased ðP , 0:003Þ in the PTH-injected group (0.7 MPa (0.1 -2.1)) compared with the vehicle-injected group (0 MPa (0 -0.4)). The histomorphometry revealed that only 3 animals of the 10 in the vehicle-injected group had trabeculae in the distal femoral metaphysis. All PTH-injected animals (12 of 12) had continuous trabecular bone network in the marrow cavity. Conclusion: Intermittent PTH treatment induced marked formation of new cancellous bone trabeculae with substantial mechanical strength, at a site where it had disappeared in old rats.

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Section: Discussionmentioning

confidence: 66%

Parathyroid hormone induces formation of new cancellous bone with substantial mechanical strength at a site where it had disappeared in old rats

Oxlund¹,

Dalstra²,

Ejersted³

et al. 2002

European Journal of Endocrinology

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“…The basic mechanisms by which exogenous PTH exerts anabolic actions in bone are still poorly understood; however, these effects have been associated with increases in osteogenic cell proliferation and differentiation [22] and prolonged osteoblast survival [ 141. Nishida et al demonstrated that cultured BMSCs isolated from rodent long bones following a 3-week regimen with anabolic doses of PTH( 1-34) generated more alkaline phosphatase positive-colony forming unit-fibroblastic colonies (CFU-F), suggesting that these cells were already committed to the osteoblastic lineage.…”

Section: Discussionmentioning

confidence: 99%

Skeletal homeostasis in tissue‐engineered bone

Schneider

Taboas

McCauley

et al. 2003

Journal Orthopaedic Research

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Tissue-engineering strategies to stimulate bone regeneration may offer an alternative approach to conventional orthopaedic and maxillofacial surgical therapies. Over the last decade, significant advances have been accomplished in developing biomimetic matrices, growth factors, cell transplantation and gene delivery therapeutics to support new bone growth. However, it is not known if tissue-engineered bone recapitulates the biology of normal skeletal tissue in response to physiologic cues. Here, we report that bone formed by the differentiation of transplanted murine bone marrow stromal cells (BMSCs) responds to a systemically delivered calciotropic hormone. Ectopic ossicles in mice exposed to catabolic doses of parathyroid hormone (PTH) had increased numbers of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts as compared to control mice. In contrast, treatment with anabolic doses of PTH promoted a marked increase in trabecular bone mass as analyzed by microcomputed tomography and histomorphometry. Our findings demonstrate that bone formed from transplanted BMSCs is responsive to normal physiologic signals, and can be augmented by the addition of a systemic anabolic agent. Because multiple and distinct ossicles can be generated in a single animal, this versatile system may be used to: (a) elucidate cellularlmolecular mechanisms in bone regeneration; (b) study cellto-cell interactions in the bone marrow microenvironment in health and disease; and (c) evaluate the efficacy of osteotropic agents that modulate bone turnover in vivo.

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“…AlkPhos + assay [15] BM was flushed from femurs; single-cell suspensions were prepared, and cells were seeded into 6-well plates at an initial density of 1 · 10 6 cells/well. Each culture well contained 2 mL of complete a-MEM supplemented with 100 IU/ mL penicillin, 100 mg/mL streptomycin, 25 mg/mL amphotericin, 2 mM l-glutamine (Hyclone Laboratories, Inc.), ascorbic acid (50 mg/mL, Sigma), and 10% fetal bovine serum (FBS; Atlanta Biologicals).…”

Section: Cfu-fmentioning

confidence: 99%

Nmp4/CIZ Suppresses the Parathyroid Hormone Anabolic Window by Restricting Mesenchymal Stem Cell and Osteoprogenitor Frequency

Childress

Hood

et al. 2013

Stem Cells and Development

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Parathyroid hormone (PTH) anabolic osteoporosis therapy is intrinsically limited by unknown mechanisms. We previously showed that disabling the transcription factor Nmp4/CIZ in mice expanded this anabolic window while modestly elevating bone resorption. This enhanced bone formation requires a lag period to materialize. Wild-type (WT) and Nmp4-knockout (KO) mice exhibited equivalent PTH-induced increases in bone at 2 weeks of treatment, but by 7 weeks, the null mice showed more new bone. At 3-week treatment, serum osteocalcin, a bone formation marker, peaked in WT mice, but continued to increase in null mice. To determine if 3 weeks is the time when the addition of new bone diverges and to investigate its cellular basis, we treated 10-week-old null and WT animals with human PTH (1-34) (30 mg/kg/day) or vehicle before analyzing femoral trabecular architecture and bone marrow (BM) and peripheral blood phenotypic cell profiles. PTH-treated Nmp4-KO mice gained over 2-fold more femoral trabecular bone than WT by 3 weeks. There was no difference between genotypes in BM cellularity or profiles of several blood elements. However, the KO mice exhibited a significant elevation in CFU-F cells, CFU-F AlkPhos + cells (osteoprogenitors), and a higher percentage of CFU-F AlkPhos + cells/CFU-F cells consistent with an increase in CD45 -/CD146 + /CD105 + /nestin + mesenchymal stem cell frequency. Null BM exhibited a 2-fold enhancement in CD8 + T cells known to support osteoprogenitor differentiation and a 1.6-fold increase in CFU-GM colonies (osteoclast progenitors). We propose that Nmp4/CIZ limits the PTH anabolic window by restricting the number of BM stem, progenitor, and blood cells that support anabolic bone remodeling.

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Increased bone formation by intermittent parathyroid hormone administration is due to the stimulation of proliferation and differentiation of osteoprogenitor cells in bone marrow

Cited by 230 publications

References 24 publications

Parathyroid hormone induces formation of new cancellous bone with substantial mechanical strength at a site where it had disappeared in old rats

Parathyroid hormone induces formation of new cancellous bone with substantial mechanical strength at a site where it had disappeared in old rats

Skeletal homeostasis in tissue‐engineered bone

Nmp4/CIZ Suppresses the Parathyroid Hormone Anabolic Window by Restricting Mesenchymal Stem Cell and Osteoprogenitor Frequency

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