Chronic psychosocial stress disturbs long-bone growth in adolescent mice

Foertsch, Sandra; Haffner‐Luntzer, Melanie; Kroner, Jochen; Groß, F; Kaiser, Kathrin; Erber, Maike; Reber, Stefan O.; Ignatius, Anita

doi:10.1242/dmm.030916

Cited by 31 publications

(28 citation statements)

References 63 publications

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“…Moreover, CSC mice display increased anxiety-related behavior (9) and increased myelopoiesis in the bone marrow (10). Importantly, we further revealed recently that cartilage-to-bone transition during growth plate endochondral ossification is disturbed in CSC versus single-housed control (SHC) mice and that catecholamines released locally in the bone marrow might underlie these negative stress consequences (11). As the process of secondary bone healing after fracture mimics the endochondral ossification process during longitudinal bone growth, we hypothesize that CSC exposure might also compromise bone fracture healing.…”

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confidence: 66%

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

Haffner‐Luntzer¹,

Foertsch

Fischer³

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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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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mentioning

confidence: 66%

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

Haffner‐Luntzer¹,

Foertsch

Fischer³

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…As previously proposed [ 38 ], the most obvious candidate system to mediate crosstalk between the left and right limbs is the nervous system. While the exact mechanism remains to be determined, a recent study showed that peripheral sympathetic nerves might inhibit bone growth in response to sustained social stress [ 40 ]. Regardless of the mechanism, these results suggest that the observed systemic growth reduction in ePit-Col-p21 embryos is a combination of 2 effects: reduced growth efficiency of the contralateral bones in response to the left-specific insult, and impairment of placental function that affects the rest of the body.…”

Section: Discussionmentioning

confidence: 99%

Cell-nonautonomous local and systemic responses to cell arrest enable long-bone catch-up growth in developing mice

et al. 2018

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Catch-up growth after insults to growing organs is paramount to achieving robust body proportions. In fly larvae, injury to individual tissues is followed by local and systemic compensatory mechanisms that allow the damaged tissue to regain normal proportions with other tissues. In vertebrates, local catch-up growth has been described after transient reduction of bone growth, but the underlying cellular responses are controversial. We developed an approach to study catch-up growth in foetal mice in which mosaic expression of the cell cycle suppressor p21 is induced in the cartilage cells (chondrocytes) that drive long-bone elongation. By specifically targeting p21 expression to left hindlimb chondrocytes, the right limb serves as an internal control. Unexpectedly, left–right limb symmetry remained normal, revealing deployment of compensatory mechanisms. Above a certain threshold of insult, an orchestrated response was triggered involving local enhancement of bone growth and systemic growth reduction that ensured that body proportions were maintained. The local response entailed hyperproliferation of spared left limb chondrocytes that was associated with reduced chondrocyte density. The systemic effect involved impaired placental function and IGF signalling, revealing bone–placenta communication. Therefore, vertebrates, like invertebrates, can mount coordinated local and systemic responses to developmental insults that ensure that normal body proportions are maintained.

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“…Tibia lengths were assessed using a digital precision caliper. Left femurs were subjected to μCT analysis as described previously ( Foertsch et al, 2017 ). Briefly, scanning was done at 50 kV and 200 mA, voxel resolution was set to 8 μm.…”

Section: Methodsmentioning

confidence: 99%

“…The “chronic subordinate colony housing” (CSC) paradigm is a well-characterized animal model for PTSD in male mice ( Reber et al, 2016a ) and causes chronic low-grade inflammation ( Langgartner et al, 2018 ), disturbance of bone homeostasis ( Foertsch et al, 2017 ), general and social anxiety ( Slattery et al, 2012 ; Langgartner et al, 2017 ), and, in the presence of colonic pathobionts like Helicobacter spp. ( Langgartner et al, 2017 ), spontaneous colitis ( Reber et al, 2007 , 2011 , 2016b ; Langgartner et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

The Role of the Intestinal Microbiome in Chronic Psychosocial Stress-Induced Pathologies in Male Mice

Langgartner

Vaihinger

Haffner‐Luntzer³

et al. 2018

Front. Behav. Neurosci.

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Chronic psychosocial stress is a risk factor for the development of physical and mental disorders accompanied or driven by an activated immune system. Given that chronic stress-induced systemic immune activation is lacking in germ-free and antibiotics-treated mice, a causal role of the gut microbiome in the development of stress-related disorders is likely. To address this hypothesis in the current study we employed the chronic subordinate colony housing (CSC, 19 days) paradigm, a pre-clinically validated mouse model for chronic psychosocial stress, known to alter the gut microbial signature and to induce systemic low-grade inflammation, as well as physical and mental abnormalities. In detail, we investigated if (i) CSC-induced alterations can be prevented by repeated transplantation of feces (FT) from non-stressed single-housed control (SHC) mice during CSC exposure, and (ii) if the transplantation of a “stressed” CSC microbiome is able to induce CSC effects in SHC mice. Therefore, we repeatedly infused SHC and CSC recipient mice rectally with SHC donor feces at days 4 and 11 of the CSC paradigm and assessed anxiety-related behavior on day 19 as well as physiological, immunological, and bone parameters on day 20. Furthermore, SHC and CSC recipient mice were infused with CSC donor feces at respective days. To exclude effects of rectal infusions per se, another set of SHC and CSC mice was infused with saline, respectively. Our results showed that transplantation of SHC feces had mild stress-protective effects, indicated by an amelioration of CSC-induced thymus atrophy, anxiety, systemic low-grade inflammation, and alterations in bone homeostasis. Moreover, transplantation of CSC feces slightly aggravated CSC-induced systemic low-grade inflammation and alterations in bone homeostasis in SHC and/or CSC animals. In conclusion, our data provide evidence for a role of the host’s microbiome in many, but not all, adverse consequences of chronic psychosocial stress. Moreover, our data are consistent with the hypothesis that transplantation of healthy feces might be a useful tool to prevent/treat different adverse outcomes of chronic stress. Finally, our data suggests that stress effects can be transferred to a certain extend via FT, proposing therapeutic approaches using FT to carefully screen fecal donors for their stress/trauma history.

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Chronic psychosocial stress disturbs long-bone growth in adolescent mice

Cited by 31 publications

References 63 publications

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

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

Cell-nonautonomous local and systemic responses to cell arrest enable long-bone catch-up growth in developing mice

The Role of the Intestinal Microbiome in Chronic Psychosocial Stress-Induced Pathologies in Male Mice

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