Effects of Early Life Stress on Bone Homeostasis in Mice and Humans

Abstract

Bone pathology is frequent in stressed individuals. A comprehensive examination of mechanisms linking life stress, depression and disturbed bone homeostasis is missing. In this translational study, mice exposed to early life stress (MSUS) were examined for bone microarchitecture (μCT), metabolism (qPCR/ELISA), and neuronal stress mediator expression (qPCR) and compared with a sample of depressive patients with or without early life stress by analyzing bone mineral density (BMD) (DXA) and metabolic changes in serum (osteocalcin, PINP, CTX-I). MSUS mice showed a significant decrease in NGF, NPYR1, VIPR1 and TACR1 expression, higher innervation density in bone, and increased serum levels of CTX-I, suggesting a milieu in favor of catabolic bone turnover. MSUS mice had a significantly lower body weight compared to control mice, and this caused minor effects on bone microarchitecture. Depressive patients with experiences of childhood neglect also showed a catabolic pattern. A significant reduction in BMD was observed in depressive patients with childhood abuse and stressful life events during childhood. Therefore, future studies on prevention and treatment strategies for both mental and bone disease should consider early life stress as a risk factor for bone pathologies.

###Reviewer #1:

The manuscript by Wuertz-Kozak et al explores the relationship between early life stress bone parameters in mice and humans. In mouse studies, micro CT and qPCR analyses were done, while in humans with depression and history of childhood neglect had bone turnover markers and DXA scans done. Increased CTX levels were noted in both mice with early life stress and in certain groups of humans with depression. These investigators recommend that early life stress be further assessed as a risk factor for human bone disease.

Although the authors acknowledge the limitations of controlling and even assessing accurately the kind of impacts (e.g., nutritional, activity-related, body weight changes, age when stress inflicted etc) that may operate during childhood stress and neglect, the human model is very problematic because of this heterogeneity. There do not appear to be good parallels between the mouse model and the human cohort.
Bone cell proliferation and differentiation are proposed to be affected in the mouse model. Proliferation can be directly measured in many ways and should be formally tested. Similarly, the stage of osteoblast differentiation can be easily assessed by PCR with well-validated gene markers of early vs late differentiation. The hypothesis proposed in line 140 can be directly tested.
What is the significance of the increased innervation that is reported in Figure 1 and the reduced neuronal receptor expression in the next figure? It would make sense that more nerve growth would lead to greater receptor expression. Is it also unexpected that NGF2 levels are so low when there is increased nerve innervation to the bone in MSUS mice?
The authors propose a 'catabolic shift' in bone in the MSUS mice. There are a few unusual things that have been reported in this matter. Most researchers would not consider osteoprotegrin a matrix gene (line 159). Furthermore, changes in osteocalcin, osteopontin and sclerostin mRNA would not be the most sensitive markers for the proposed catabolic shift. The proteins encoded by these genes are in the matrix but they are the products of osteoblasts and osteocytes and the bone formation marker P1NP per the authors is unchanged in the mice. It is the CTX that is elevated and perhaps more sensitive gene markers for a catabolic shift would be RANK-ligand, mCSF and perhaps osteoclastic genes.
The Descriptive Result for the Human Study (line 172-184) is very difficult to follow. Many more key demographic, biochemical, and clinical characteristics of the human study populations need to be provided. The paper uses a wide age range of patients (18-65 years). Therefore some of the subjects will have gone through menopause and others who may not yet have reached peak BMD. This introduces a great deal of heterogeneity into the population being studied.
What was the exposure and duration of the use of SSRI's in the population? These medications are implicated in reduced BMD and increased fracture rates in some studies.
DXA results: (a) What site in the hip DXA is "H" or "collum femoris"? (b) One would have suspected that the total hip BMD and femoral neck BMD would have aligned with the results for the greater trochanter BMD, as shown in Table 1. Yet the 3 sites in the hip do not align. This suggests a weak relationship. (c) Lines 179-181, it seems that only ~33 subjects were included in the DXA studies. Given the heterogeneity of the population being studied in key parameters - age, sex etc - this would be an extremely small number to break into 4 groups as in Table 1, run statistical testing on, and report out on BMD results. This is a very under-powered study. BMD varies with age, sex, ethnicity, body size. Such characteristics need to be controlled to tease out an effect of childhood trauma and depression on bone.
Micro CT data in the MSUS mice are driven by effects on body weight, and these data do not support a direct effect of postnatal stress on the bone itself.
The human cohort needs to be better defined and described. It likely should not cover such a wide age range (18-65 years). Drug therapies for depression and their duration should be specified to compare the groups. A thorough medical assessment needs to be done on these subjects with screening labs and a basic screening medical history and physical examination. Many disorders known to affect bone could be missed (e.g., menopause, liver or kidney disease, etc). Alcohol consumption needs to be explored and clearly reported as well as the amount of smoking since both habits affect bone parameters.

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Effects of Early Life Stress on Bone Homeostasis in Mice and Humans

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