Towards in silico Models of the Inflammatory Response in Bone Fracture Healing

In silico modeling is a powerful strategy to investigate the biological events occurring at tissue, cellular and subcellular level during bone fracture healing. However, most current models do not consider the impact of the inflammatory response on the later stages of bone repair. Indeed, as initiator of the healing process, this early phase can alter the regenerative outcome: if the inflammatory response is too strongly down- or upregulated, the fracture can result in a non-union. This review covers the fundamental information on fracture healing, in silico modeling and experimental validation. It starts with a description of the biology of fracture healing, paying particular attention to the inflammatory phase and its cellular and subcellular components. We then discuss the current state-of-the-art regarding in silico models of the immune response in different tissues as well as the bone regeneration process at the later stages of fracture healing. Combining the aforementioned biological and computational state-of-the-art, continuous, discrete and hybrid modeling technologies are discussed in light of their suitability to capture adequately the multiscale course of the inflammatory phase and its overall role in the healing outcome. Both in the establishment of models as in their validation step, experimental data is required. Hence, this review provides an overview of the different in vitro and in vivo set-ups that can be used to quantify cell- and tissue-scale properties and provide necessary input for model credibility assessment. In conclusion, this review aims to provide hands-on guidance for scientists interested in building in silico models as an additional tool to investigate the critical role of the inflammatory phase in bone regeneration.

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Chronic psychosocial stress compromises the immune response and endochondral ossification during bone fracture healing via β-AR signaling

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1819218116 ◽

2019 ◽

Vol 116 (17) ◽

pp. 8615-8622 ◽

Cited By ~ 11

Author(s):

Melanie Haffner-Luntzer ◽

Sandra Foertsch ◽

Verena Fischer ◽

Katja Prystaz ◽

Miriam Tschaffon ◽

...

Keyword(s):

Immune Response ◽

Inflammatory Response ◽

Fracture Healing ◽

Bone Fracture ◽

Psychosocial Stress ◽

Modern Society ◽

Bone Fracture Healing ◽

Fracture Callus ◽

Chronic Psychosocial Stress ◽

Late Stages

Chronic psychosocial stress/trauma represents an increasing burden in our modern society and a risk factor for the development of mental disorders, including posttraumatic stress disorder (PTSD). PTSD, in turn, is highly comorbid with a plethora of inflammatory disorders and has been associated with increased bone fracture risk. Since a balanced inflammatory response after fracture is crucial for successful bone healing, we hypothesize that stress/trauma alters the inflammatory response after fracture and, consequently, compromises fracture healing. Here we show, employing the chronic subordinate colony housing (CSC) paradigm as a clinically relevant mouse model for PTSD, that mice subjected to CSC displayed increased numbers of neutrophils in the early fracture hematoma, whereas T lymphocytes and markers for cartilage-to-bone transition and angiogenesis were reduced. At late stages of fracture healing, CSC mice were characterized by decreased bending stiffness and bony bridging of the fracture callus. Strikingly, a single systemic administration of the β-adrenoreceptor (AR) blocker propranolol before femur osteotomy prevented bone marrow mobilization of neutrophils and invasion of neutrophils into the fracture hematoma, both seen in the early phase after fracture, as well as a compromised fracture healing in CSC mice. We conclude that chronic psychosocial stress leads to an imbalanced immune response after fracture via β-AR signaling, accompanied by disturbed fracture healing. These findings offer possibilities for clinical translation in patients suffering from PTSD and fracture.

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In silico design of treatment strategies in wound healing and bone fracture healing

Philosophical Transactions of The Royal Society A Mathematical Physical and Engineering Sciences ◽

10.1098/rsta.2010.0056 ◽

2010 ◽

Vol 368 (1920) ◽

pp. 2683-2706 ◽

Cited By ~ 23

Author(s):

L. Geris ◽

R. Schugart ◽

H. Van Oosterwyck

Keyword(s):

Mathematical Models ◽

Fracture Healing ◽

Bone Fracture ◽

In Silico ◽

Healing Process ◽

Treatment Strategies ◽

Experimental Models ◽

Bone Fracture Healing ◽

Impaired Healing ◽

Healing Processes

Wound and bone fracture healing are natural repair processes initiated by trauma. Over the last decade, many mathematical models have been established to investigate the healing processes in silico , in addition to ongoing experimental work. In recent days, the focus of the mathematical models has shifted from simulation of the healing process towards simulation of the impaired healing process and the in silico design of treatment strategies. This review describes the most important causes of failure of the wound and bone fracture healing processes and the experimental models and methods used to investigate and treat these impaired healing cases. Furthermore, the mathematical models that are described address these impaired healing cases and investigate various therapeutic scenarios in silico . Examples are provided to illustrate the potential of these in silico experiments. Finally, limitations of the models and the need for and ability of these models to capture patient specificity and variability are discussed.

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Histone demethylase LSD1 is critical for endochondral ossification during bone fracture healing

Science Advances ◽

10.1126/sciadv.aaz1410 ◽

2020 ◽

Vol 6 (45) ◽

pp. eaaz1410

Author(s):

Jun Sun ◽

Heng Feng ◽

Wenhui Xing ◽

Yujiao Han ◽

Jinlong Suo ◽

...

Keyword(s):

Retinoic Acid ◽

Fracture Healing ◽

Bone Regeneration ◽

Bone Fracture ◽

Endochondral Ossification ◽

Callus Formation ◽

Critical Factor ◽

Fracture Repair ◽

Retinoic Acid Signaling ◽

Bone Fracture Healing

Bone fracture is repaired predominantly through endochondral ossification. However, the regulation of endochondral ossification by key factors during fracture healing remains largely enigmatic. Here, we identify histone modification enzyme LSD1 as a critical factor regulating endochondral ossification during bone regeneration. Loss of LSD1 in Prx1 lineage cells severely impaired bone fracture healing. Mechanistically, LSD1 tightly controls retinoic acid signaling through regulation of Aldh1a2 expression level. The increased retinoic acid signaling in LSD1-deficient mice suppressed SOX9 expression and impeded the cartilaginous callus formation during fracture repair. The discovery that LSD1 can regulate endochondral ossification during fracture healing will benefit the understanding of bone regeneration and have implications for regenerative medicine.

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