PMID- 11455125
OWN - NLM
STAT- MEDLINE
DCOM- 20011011
LR  - 20220309
IS  - 1422-6405 (Print)
IS  - 1422-6405 (Linking)
VI  - 169
IP  - 3
DP  - 2001
TI  - Impaired intramembranous bone formation during bone repair in the absence of 
      tumor necrosis factor-alpha signaling.
PG  - 285-94
AB  - Tumor necrosis factor-alpha (TNF-alpha) is known to mediate bone resorption; 
      however, its role in osteogenesis has not been fully elucidated. In order to 
      investigate the direct role of TNF-alpha signaling in the recruitment and 
      differentiation of osteoblasts, two separate models of bone repair were used, 
      marrow ablation and simple transverse fractures. These models were carried out in 
      the tibiae of both wild-type and knock-out mice in which both TNF-alpha receptors 
      (p55(-/-)/p75(-/-)) had been ablated. Marrow ablation is a unique model in which 
      robust intramembranous bone formation is induced without an endochondral 
      component, followed by remodeling and restoration of the original trabecular 
      architecture of the bone marrow. In contrast, fracture repair proceeds 
      concurrently through both endochondral and intramembranous processes of new bone 
      tissue formation. In both models of bone repair, healing was delayed in the 
      TNF-alpha receptor (p55(-/-)/p75(-/-)) deficient mice. In the marrow ablation 
      model, young osteoblasts were recruited into the marrow space by day three in the 
      wild-type mice, while the TNF-alpha (p55(-/-)/p75(-/-)) mice had only granulation 
      tissue in the marrow cavity. Type I collagen and osteocalcin mRNA expressions 
      were reduced approximately 30 and approximately 50%, respectively, of the control 
      values in the TNF-alpha receptor ablated mice. In the fracture repair model there 
      was almost a complete absence of the initial intramembranous bone formation on 
      the periosteal surface in the TNF-alpha (p55(-/-)/p75(-/-)) mice. As healing 
      progressed however, the callus tissues were greatly enlarged, and there was a 
      delay in hypertrophy of the chondrocytes and the resorption of cartilage tissue. 
      While during the initial period of fracture repair there was a marked reduction 
      in the expression of both type I collagen and osteocalcin mRNAs in the TNF-alpha 
      (p55(-/-)/p75(-/-)) mice, levels of these mRNAs were elevated by approximately 
      10-20% over the wild type at the later time points in the absence of endochondral 
      resorption of the callus. The lack of inhibition of osteogenesis during 
      endochondral resorption suggests that a different set of signals are involved in 
      the recruitment of osteogenic cells during endochondral repair then during 
      intramembranous bone formation. Co-culture of chondrocytes with a mesenchymal 
      stem cell line was carried out to examine if chondrocytes themselves produced 
      paracrine factors that promote osteogenic differentiation. These experiments 
      demonstrated that chondrocytes do indeed produce factors that promoted osteogenic 
      differentiation. In summary, the results presented here suggest that TNF-alpha 
      plays a crucial role in promoting postnatal bone repair through the induction of 
      osteoprogenitor cell recruitment or osteogenic cell activation in the context of 
      intramembranous bone formation. These results further suggest that the signals 
      that promote osteogenesis during endochondral bone formation are different from 
      those involved in intramembranous bone formation.
CI  - Copyright 2001 S. Karger AG, Basel.
FAU - Gerstenfeld, L C
AU  - Gerstenfeld LC
AD  - Department of Orthopaedic Surgery, Boston University Medical Center, Boston, 
      Mass., USA. lgersten@bu.edu
FAU - Cho, T J
AU  - Cho TJ
FAU - Kon, T
AU  - Kon T
FAU - Aizawa, T
AU  - Aizawa T
FAU - Cruceta, J
AU  - Cruceta J
FAU - Graves, B D
AU  - Graves BD
FAU - Einhorn, T A
AU  - Einhorn TA
LA  - eng
PT  - Journal Article
PL  - Switzerland
TA  - Cells Tissues Organs
JT  - Cells, tissues, organs
JID - 100883360
RN  - 0 (Antigens, CD)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Tumor Necrosis Factor)
RN  - 0 (Receptors, Tumor Necrosis Factor, Type I)
RN  - 0 (Receptors, Tumor Necrosis Factor, Type II)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 104982-03-8 (Osteocalcin)
RN  - 9007-34-5 (Collagen)
RN  - EC 1.2.1.- (Glyceraldehyde-3-Phosphate Dehydrogenases)
SB  - IM
MH  - Animals
MH  - Antigens, CD/genetics/physiology
MH  - Collagen/genetics
MH  - Fracture Healing/genetics/*physiology
MH  - Gene Expression
MH  - Glyceraldehyde-3-Phosphate Dehydrogenases/genetics
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Osteocalcin/genetics
MH  - Osteogenesis/genetics/*physiology
MH  - RNA, Messenger/genetics/metabolism
MH  - Receptors, Tumor Necrosis Factor/genetics/physiology
MH  - Receptors, Tumor Necrosis Factor, Type I
MH  - Receptors, Tumor Necrosis Factor, Type II
MH  - Signal Transduction
MH  - Tumor Necrosis Factor-alpha/*physiology
EDAT- 2001/07/17 10:00
MHDA- 2001/10/12 10:01
CRDT- 2001/07/17 10:00
PHST- 2001/07/17 10:00 [pubmed]
PHST- 2001/10/12 10:01 [medline]
PHST- 2001/07/17 10:00 [entrez]
AID - 47893 [pii]
AID - 10.1159/000047893 [doi]
PST - ppublish
SO  - Cells Tissues Organs. 2001;169(3):285-94. doi: 10.1159/000047893.