Osteoblast-specific overexpression of complement receptor C5aR1 impairs fracture healing
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Osteoblast-specific overexpression of complement receptor C5aR1 impairs fracture healing. / Bergdolt, Stephanie; Kovtun, Anna; Hägele, Yvonne; Liedert, Astrid; Schinke, Thorsten; Amling, Michael; Huber-Lang, Markus; Ignatius, Anita.
In: PLOS ONE, Vol. 12, No. 6, 14.06.2017, p. e0179512.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Osteoblast-specific overexpression of complement receptor C5aR1 impairs fracture healing
AU - Bergdolt, Stephanie
AU - Kovtun, Anna
AU - Hägele, Yvonne
AU - Liedert, Astrid
AU - Schinke, Thorsten
AU - Amling, Michael
AU - Huber-Lang, Markus
AU - Ignatius, Anita
PY - 2017/6/14
Y1 - 2017/6/14
N2 - The anaphylatoxin receptor C5aR1 plays an important role not only in innate immune responses, but also in bone metabolism and fracture healing, being highly expressed on immune and bone cells, including osteoblasts and osteoclasts. C5aR1 induces osteoblast migration, cytokine generation and osteoclastogenesis, however, the exact role of C5aR1-mediated signaling in osteoblasts is not entirely known. Therefore, we hypothesized that osteoblasts are essential target cells for C5a and that fracture healing should be disturbed in mice with an osteoblast-specific C5aR1 overexpression (Col1a1-C5aR1). Osteoblast activity in vitro, bone phenotype and fracture healing after isolated osteotomy and after combined osteotomy with additional thoracic trauma were analyzed. The systemic and local inflammatory reactions were analyzed by determining C5a and IL-6 concentrations in blood, bronchoalveolar lavage fluid and fracture callus and the recruitment of immune cells. In vitro, osteoblast proliferation and differentiation were similar to wildtype cells, and phosphorylation of p38 and expression of IL-6 and RANKL were increased in osteoblasts derived from Col1a1-C5aR1 mice. Bone phenotype and the inflammatory reaction were unaffected in Col1a1-C5aR1 mice. Fracture healing was significantly impaired as demonstrated by significantly reduced bone content, bone mineral density and flexural rigidity, possibly due to significantly increased osteoclast numbers. C5aR1 signaling in osteoblasts might possibly affect RANKL/OPG balance, leading to increased bone resorption. Additional trauma significantly impaired fracture healing, particularly in Col1a1-C5aR1 mice. In conclusion, the data indicate that C5aR1 signaling in osteoblasts plays a detrimental role in bone regeneration after fracture.
AB - The anaphylatoxin receptor C5aR1 plays an important role not only in innate immune responses, but also in bone metabolism and fracture healing, being highly expressed on immune and bone cells, including osteoblasts and osteoclasts. C5aR1 induces osteoblast migration, cytokine generation and osteoclastogenesis, however, the exact role of C5aR1-mediated signaling in osteoblasts is not entirely known. Therefore, we hypothesized that osteoblasts are essential target cells for C5a and that fracture healing should be disturbed in mice with an osteoblast-specific C5aR1 overexpression (Col1a1-C5aR1). Osteoblast activity in vitro, bone phenotype and fracture healing after isolated osteotomy and after combined osteotomy with additional thoracic trauma were analyzed. The systemic and local inflammatory reactions were analyzed by determining C5a and IL-6 concentrations in blood, bronchoalveolar lavage fluid and fracture callus and the recruitment of immune cells. In vitro, osteoblast proliferation and differentiation were similar to wildtype cells, and phosphorylation of p38 and expression of IL-6 and RANKL were increased in osteoblasts derived from Col1a1-C5aR1 mice. Bone phenotype and the inflammatory reaction were unaffected in Col1a1-C5aR1 mice. Fracture healing was significantly impaired as demonstrated by significantly reduced bone content, bone mineral density and flexural rigidity, possibly due to significantly increased osteoclast numbers. C5aR1 signaling in osteoblasts might possibly affect RANKL/OPG balance, leading to increased bone resorption. Additional trauma significantly impaired fracture healing, particularly in Col1a1-C5aR1 mice. In conclusion, the data indicate that C5aR1 signaling in osteoblasts plays a detrimental role in bone regeneration after fracture.
KW - Animals
KW - Blotting, Western
KW - Bronchoalveolar Lavage Fluid
KW - Cells, Cultured
KW - Collagen Type I
KW - Complement C5a
KW - Femur
KW - Fracture Healing
KW - Gene Expression Regulation
KW - Interleukin-6
KW - Mice
KW - Osteoblasts
KW - Osteogenesis
KW - Osteoprotegerin
KW - Phosphorylation
KW - RANK Ligand
KW - Receptor, Anaphylatoxin C5a
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Signal Transduction
KW - Up-Regulation
KW - X-Ray Microtomography
KW - p38 Mitogen-Activated Protein Kinases
KW - Journal Article
U2 - 10.1371/journal.pone.0179512
DO - 10.1371/journal.pone.0179512
M3 - SCORING: Journal article
C2 - 28614388
VL - 12
SP - e0179512
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 6
ER -
