Immunologicalization of complement C1s and matrix metalloproteinase 9 (92kDa gelatinase/type IV collagenase) in the primary ossification center of the human femur

Sakiyama, Hisako; Inaba, Noriyuki; Toyoguchi, Toru; Okada, Yasunori; Matsumoto, Misako; Moriya, Hideshige; Ohtsu, Hiroshi

doi:10.1007/bf00327771

Cited by 30 publications

(15 citation statements)

References 27 publications

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“…The initiating enzyme of the classical pathway, C1s, has been localized to hypertrophic chondrocytes within the primary ossification center of the femur, and its collagen-degrading activity has been linked to matrix degradation during endochondral bone formation [77]. Primary osteoblasts secrete C3 in response to 1α,2,5-dihydroxyvitamin D 3 , and C3 also appears to synergistically promote M-CSF-dependent osteoclast differentiation from bone marrow progenitors [78].…”

Section: Complement In Mammalian Regenerative Processesmentioning

confidence: 99%

Complement-triggered pathways orchestrate regenerative responses throughout phylogenesis

Mastellos

DeAngelis

Lambris

2013

Seminars in Immunology

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Adult tissue plasticity, cell reprogramming, and organ regeneration are major challenges in the field of modern regenerative medicine. Devising strategies to increase the regenerative capacity of tissues holds great promise for dealing with donor organ shortages and low transplantation outcomes and also provides essential impetus to tissue bioengineering approaches for organ repair and replacement. The inherent ability of cells to reprogram their fate by switching into an embryonic-like, pluripotent progenitor state is an evolutionary vestige that in mammals has been retained mostly in fetal tissues and persists only in a few organs of the adult body. Tissue regeneration reflects the capacity of terminally differentiated cells to re-enter the cell cycle and proliferate in response to acute injury or environmental stress signals. In lower vertebrates, this regenerative capacity extends to several organs and remarkably culminates in precise tissue patterning, through cellular transdifferentiation and complex morphogenetic processes that can faithfully reconstruct entire body parts. Many lessons have been learned from robust regeneration models in amphibians such as the newt and axolotl. However, the dynamic interactions between the regenerating tissue, the surrounding stroma, and the host immune response, as it adapts to the actively proliferating tissue, remain ill-defined. The regenerating zone, through a sequence of distinct molecular events, adopts phenotypic plasticity and undergoes rigorous tissue remodeling that, in turn, evokes a significant inflammatory response. Complement is a primordial sentinel of the innate immune response that engages in multiple inflammatory cascades as it becomes activated during tissue injury and remodeling. In this respect, complement proteins have been implicated in tissue and organ regeneration in both urodeles and mammals. Distinct complement-triggered pathways have been shown to modulate critical responses that promote tissue reprogramming, pattern formation, and regeneration across phylogenesis. This article will discuss the mechanistic insights underlying the crosstalk of complement with cytokine and growth factor signaling pathways that drive tissue regeneration and will provide a unified conceptual framework for considering complement modulation as a novel target for regenerative therapeutics.

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Section: Complement In Mammalian Regenerative Processesmentioning

confidence: 99%

Complement-triggered pathways orchestrate regenerative responses throughout phylogenesis

Mastellos

DeAngelis

Lambris

2013

Seminars in Immunology

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“…Recent studies were able to provide first evidence for an involvement of complement in bone biology [19–21]. …”

Section: Discussionmentioning

confidence: 99%

C5aR inhibition in the early inflammatory phase does not affect bone regeneration in a model of uneventful fracture healing

et al. 2016

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BackgroundRecent studies were able to demonstrate involvement of the complement cascade in bone biology. Further studies analyzed the role of complement in traumatic injuries and demonstrated negative effects after excessive systemic activation of the inflammatory response with early abrogation of complement activation after application of a C5aR-antagonist exerting beneficial effects upon bone regeneration. In contrast, own fracture healing experiments with complement-deficient animals implied a crucial role of the complement cascade for sufficient fracture healing.MethodsTo analyze the effect of a short abrogation of the complement system in the local process of fracture healing, a fracture healing experiment with wild-type mice (C57BL6), femoral osteotomy, consecutive external fixation for 21 days and blockade of the early complement activation (C5aRA) directly after trauma and after 12 h was performed. Control animals received a peptide without any biological effects. After 1–3 days, the inflammatory response was monitored with IL-6 immunostaining, serum analyses of C5a and after 3 days with histological evaluation of PMN. Fracture healing was examined with biomechanical, radiological and histological methods after 21 days.ResultsWhile a decrease of the early inflammatory response was seen on day 1 of the C5aRA-treated group regarding immunostaining for IL-6 and after 3 days in the histological evaluation of PMN, no significant differences were demonstrated between both experimental groups after 21 days in the biomechanical, radiological and histological evaluation.ConclusionsThe present results demonstrate that the short-term inhibition of complement activation immediately after fracture does not significantly affect bone regeneration in an experimental model of regular fracture healing. Whereas other studies demonstrated that the early posttraumatic blockade of the C5aR improves fracture healing in a scenario of combined trauma, the present findings implicate that the same treatment has no effect in uneventful bone healing.

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“…C1s possesses the ability to degrade Type 1 and 2 collagen [44]. Immunohistochemical analysis of the primary ossification center of the human femur revealed that C1s co-localizes with MMP-9 throughout this region, including hypertrophic chondrocytes, mesenchymal cells and the extracellular matrix [44].…”

Section: The Complement Cascade and Cellular Growth And Regenerationmentioning

confidence: 99%

“…Immunohistochemical analysis of the primary ossification center of the human femur revealed that C1s co-localizes with MMP-9 throughout this region, including hypertrophic chondrocytes, mesenchymal cells and the extracellular matrix [44]. C1s can also cleave the zymogen of MMP-9 and activate its protease activity [44]. Their co-localization implies a coordinated role in the turnover of cartilage to bone [44].…”

Section: The Complement Cascade and Cellular Growth And Regenerationmentioning

confidence: 99%

The complement cascade as a mediator of tissue growth and regeneration

et al. 2010

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Recent evidence has demonstrated that the complement cascade is involved in a variety of physiologic and pathophysiologic processes in addition to its role as an immune effector. Research in a variety of organ systems has shown that complement proteins are direct participants in maintenance of cellular turnover, healing, proliferation and regeneration. As a physiologic housekeeper, complement proteins maintain tissue integrity in the absence of inflammation by disposing of cellular debris and waste, a process critical to the prevention of autoimmune disease. Developmentally, complement proteins influence pathways including hematopoietic stem cell engraftment, bone growth, and angiogenesis. They also provide a potent stimulus for cellular proliferation including regeneration of the limb and eye in animal models, and liver proliferation following injury. Here, we describe the complement cascade as a mediator of tissue growth and regeneration.

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Immunologicalization of complement C1s and matrix metalloproteinase 9 (92kDa gelatinase/type IV collagenase) in the primary ossification center of the human femur

Cited by 30 publications

References 27 publications

Complement-triggered pathways orchestrate regenerative responses throughout phylogenesis

Complement-triggered pathways orchestrate regenerative responses throughout phylogenesis

C5aR inhibition in the early inflammatory phase does not affect bone regeneration in a model of uneventful fracture healing

The complement cascade as a mediator of tissue growth and regeneration

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