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

doi:10.1371/journal.pone.0179512

Cited by 27 publications

(36 citation statements)

References 40 publications

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“…Total RNA isolation and RT‐PCR were performed as described previously . Gene expression was analysed relative to the housekeeping gene glyceraldehyde‐3‐phosphate dehydrogenase ( Gapdh ) using the ΔΔCt method.…”

Section: Methodsmentioning

confidence: 99%

“…Moreover, we previously demonstrated that C5aR1 was strongly expressed in osteoblasts in response to bone injury, and that bone fracture healing in a rodent model of severe systemic inflammation significantly improved when treated with a small peptide C5aR1 antagonist . In this setting, osteoblasts were found to be target cells for C5a, because mice with an osteoblast‐specific C5aR1 overexpression displayed impaired fracture healing …”

Section: Introductionmentioning

confidence: 99%

“…Bone tissue is continuously rebuilt during bone remodelling, a dynamic balance between bone‐forming osteoblasts and bone‐resorbing osteoclasts, which is essential for maintaining bone mass. Interestingly, osteoblasts strongly upregulate C5aR1 expression during differentiation, indicating an important function in these cells . Indeed, in osteoblasts C5a induces migration and expression of the inflammatory cytokines interleukin‐6 (IL‐6) and IL‐8, and receptor activator of nuclear factor kappa B ligand (RANKL), which is essential for osteoclast formation and activity .…”

Section: Introductionmentioning

confidence: 99%

“…indicating an important function in these cells. 5,6 Indeed, in osteoblasts C5a induces migration and expression of the inflammatory cytokines interleukin-6 (IL-6) and IL-8, and receptor activator of nuclear factor kappa B ligand (RANKL), which is essential for osteoclast formation and activity. 5,7 Moreover, C5aR1-knockout (-ko) mice display reduced osteoclast numbers and significantly increased bone mass, suggesting that C5a/C5aR1 signalling might regulate physiological bone turnover.…”

mentioning

confidence: 99%

“…12 In this setting, osteoblasts were found to be target cells for C5a, because mice with an osteoblast-specific C5aR1 overexpression displayed impaired fracture healing. 6 However, the molecular mechanisms underlying the C5a/C5aR1 signalling axis in osteoblasts remain unclear, also in respect of potential cross-talking signalling pathways, which can modulate or are modulated by C5aR1 actions. In immune cells, C5aR1 has been described to interact with other immune receptors, including receptors for immunoglobulin G (IgG) antibodies, the FcγRs, 13 or with other biological systems, including the coagulation cascade.…”

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confidence: 99%

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C5aR1 interacts with TLR2 in osteoblasts and stimulates the osteoclast‐inducing chemokine CXCL10

Mödinger

Rapp

Pázmándi

et al. 2018

J Cellular Molecular Medi

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The anaphylatoxin C5a is generated upon activation of the complement system, a crucial arm of innate immunity. C5a mediates proinflammatory actions via the C5a receptor C5aR1 and thereby promotes host defence, but also modulates tissue homeostasis. There is evidence that the C5a/C5aR1 axis is critically involved both in physiological bone turnover and in inflammatory conditions affecting bone, including osteoarthritis, periodontitis, and bone fractures. C5a induces the migration and secretion of proinflammatory cytokines of osteoblasts. However, the underlying mechanisms remain elusive. Therefore, in this study we aimed to determine C5a‐mediated downstream signalling in osteoblasts. Using a whole‐genome microarray approach, we demonstrate that C5a activates mitogen‐activated protein kinases (MAPKs) and regulates the expression of genes involved in pathways related to insulin, transforming growth factor‐β and the activator protein‐1 transcription factor. Interestingly, using coimmunoprecipitation, we found an interaction between C5aR1 and Toll‐like receptor 2 (TLR2) in osteoblasts. The C5aR1‐ and TLR2‐signalling pathways converge on the activation of p38 MAPK and the generation of C‐X‐C motif chemokine 10, which functions, among others, as an osteoclastogenic factor. In conclusion, C5a‐stimulated osteoblasts might modulate osteoclast activity and contribute to immunomodulation in inflammatory bone disorders.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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C5aR1 interacts with TLR2 in osteoblasts and stimulates the osteoclast‐inducing chemokine CXCL10

Mödinger

Rapp

Pázmándi

et al. 2018

J Cellular Molecular Medi

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Mast Cells Trigger Disturbed Bone Healing in Osteoporotic Mice

Fischer¹,

Ragipoglu²,

Diedrich³

et al. 2020

Journal of Bone and Mineral Research

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Mast cells are important tissue-resident sensor and effector immune cells but also play a major role in osteoporosis development. Mast cells are increased in numbers in the bone marrow of postmenopausal osteoporotic patients, and mast cell-deficient mice are protected from ovariectomy (OVX)-induced bone loss. In this study, we showed that mast cell-deficient Mcpt5-Cre R-DTA mice were protected from OVX-induced disturbed fracture healing, indicating a critical role for mast cells in the pathomechanisms of impaired bone repair under estrogen-deficient conditions. We revealed that mast cells trigger the fracture-induced inflammatory response by releasing inflammatory mediators, including interleukin-6, midkine (Mdk), and C-X-C motif chemokine ligand 10 (CXCL10), and promote neutrophil infiltration into the fracture site in OVX mice. Furthermore, mast cells were responsible for reduced osteoblast and increased osteoclast activities in OVX mice callus, as well as increased receptor activator of NF-κB ligand serum levels in OVX mice. Additional in vitro studies with human cells showed that mast cells stimulate osteoclastogenesis by releasing the osteoclastogenic mediators Mdk and CXCL10 in an estrogen-dependent manner, which was mediated via the estrogen receptor alpha on mast cells. In conclusion, mast cells negatively affect the healing of bone fractures under estrogen-deficient conditions. Hence, targeting mast cells might provide a therapeutic strategy to improve disturbed bone repair in postmenopausal osteoporosis.

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Pharmacological inhibition of IL-6 trans-signaling improves compromised fracture healing after severe trauma

Kaiser¹,

Prystaz²,

Vikman³

et al. 2018

Naunyn-Schmiedeberg's Arch Pharmacol

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Patients with multiple injuries frequently suffer bone fractures and are at high risk to develop fracture healing complications. Because of its key role both in systemic posttraumatic inflammation and fracture healing, the pleiotropic cytokine interleukin-6 (IL-6) may be involved in the pathomechanisms of trauma-induced compromised fracture healing. IL-6 signals are transmitted by two different mechanisms: classic signaling via the membrane-bound receptor (mIL-6R) and trans-signaling via its soluble form (sIL-6R). Herein, we investigated whether IL-6 classic and trans-signaling play different roles in bone regeneration after severe injury. Twelve-week-old C57BL/6J mice underwent combined femur osteotomy and thoracic trauma. To study the function of IL-6, either an anti-IL-6 antibody, which inhibits both IL-6 classic and trans-signaling, or a soluble glycoprotein 130 fusion protein (sgp130Fc), which selectively blocks trans-signaling, were injected 30 min and 48 h after surgery. Bone healing was assessed using cytokine analyses, flow cytometry, histology, micro-computed tomography, and biomechanical testing. Selective inhibition of IL-6 trans-signaling significantly improved the fracture healing outcome after combined injury, as confirmed by accelerated cartilage-to-bone transformation, enhanced bony bridging of the fracture gap and improved mechanical callus properties. In contrast, global IL-6 inhibition did not affect compromised fracture healing. These data suggest that classic signaling may mediate beneficial effects on bone repair after severe injury. Selective inhibition of IL-6 trans-signaling might have therapeutic potential to treat fracture healing complications in patients with concomitant injuries.Electronic supplementary materialThe online version of this article (10.1007/s00210-018-1483-7) contains supplementary material, which is available to authorized users.

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Osteoblast-specific overexpression of complement receptor C5aR1 impairs fracture healing

Cited by 27 publications

References 40 publications

C5aR1 interacts with TLR2 in osteoblasts and stimulates the osteoclast‐inducing chemokine CXCL10

C5aR1 interacts with TLR2 in osteoblasts and stimulates the osteoclast‐inducing chemokine CXCL10

Mast Cells Trigger Disturbed Bone Healing in Osteoporotic Mice

Pharmacological inhibition of IL-6 trans-signaling improves compromised fracture healing after severe trauma

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