It is the main aim of this project to investigate in preclinical and clinical studies the cellular, molecular and microbiome-related mechanisms underlying the sex-specific effects of chronic psychosocial stress during early life (=early life adversity, ELA), adulthood (CAS) and a combination of both (ELA&CAS) on bone homeostasis and regeneration. Note, with respect to ELA we study the effects of stressors occurring during the prenatal and postnatal phase on both male and female offspring and their mothers.

Background: Chronic psychosocial stress during adulthood(1, 2) as well as early life adversity (ELA)(3-7) are acknowledged risk factors for several psychosomatic disorders, including posttraumatic stress disorder (PTSD) and major depression (MD). Both diseases display a high prevalence in western countries, are strongly comorbid with various somatic pathologies(8, 9) and have been associated with osteoporosis and increased bone fracture risk in a number of studies.(8-12). However, while there is strong evidence for an increased risk for low bone mass and fragility fractures in depressed patients being mediated by increased glucocorticoid (GC) concentrations,(13, 14) findings in PTSD patients are less consistent. For example, multivariable analyses controlling for depression in PTSD subjects failed to demonstrate a link between PTSD and osteoporosis,(15) whereas earlier studies stated a significant association between these conditions.(12) Furthermore, PTSD may influence long-bone growth: children subjected to repeated mental traumatization during childhood were of a significantly shorter stature.(16) In summary, these clinical studies implicate different effects of stress-induced depression and PTSD on bone turnover.

Main findings: In contrast to mouse models for depression, employing the chronic subordinate colony housing (CSC) paradigm as an acknowledged model for social stress-associated PTSD in male mice(17, 18) we showed that mental traumatization in adolescent mice negatively impacts cartilage-to-bone transition during endochondral ossification in the epiphyseal growth plate, the main site of longitudinal growth of the long bones, while appositional bone growth seems to be undisturbed.(19) In detail, CSC mice show reduced tibia and femur lengths, mineral deposition at the growth plate and Runt-related transcription factor 2 (Runx2) expression in hypertrophic chondrocytes in the growth plate, while growth plate and trabecular thickness as well as bone mineral density (BMD) were increased in CSC compared to single-housed control (SHC) mice.(19) An enhanced tyrosine hydroxylase (TH) expression, which is the rate limiting enzyme in catecholamine (CA) synthesis,(20) in bone marrow (BM) cells located at the growth plates of CSC mice suggests that local CA signalling is involved in the negative CSC effects on bone metabolism.(19) Of note in this context, norepinephrine (NE) release by sympathetic nerve fibers during chronic variable stress signals bone marrow niche cells to decrease CXCL12 levels through the β3-adrenoreceptor, resulting in increased hematopoietic stem cell proliferation and release of neutrophils and inflammatory monocytes.(21) In a follow up study we extended these findings by revealing that CSC mice undergoing standardized femur fracture show a delayed bone healing, again accompanied by a compromised cartilage-to-bone transition. Furthermore, CSC mice were characterized by a misbalanced inflammatory response in the fracture hematoma.(22) The latter was indicated by increased numbers of TH expressing neutrophils, and both delayed fracture healing and hematoma invasion of TH expressing neutrophils were prevented in CSC mice by injection with an unspecific β-adrenoceptor blocker prior to fracture surgery.(22) In a recent study(23) we provide evidence supporting the conclusion that while impaired mental health and stress in general promotes BM myelopoiesis, TH expression and, consequently, the capacity to produce/ secrete CAs is specifically facilitated in neutrophils. Neutrophil-derived CAs locally in the BM activate α (in vitro data)/β2 (in vitro and in vivo data)-ARs and dopaminergic receptors (DRs, in vitro data) on chondrocytes and, consequently, compromise their transdifferentiation into osteoblasts and, thus, bone metabolism. Neutrophil-derived CAs in an autocrine manner further promote their own BM emigration and, in case of a fracture, facilitate their own immigration into the fracture hematoma, likely in a paracrine manner by increasing CXCL1 release from hematoma mast cells and macrophages which are two main CXCL1 producing cell types.(24) In the fracture hematoma, neutrophil-derived CAs again activate α/β2-ARs and DRs on chondrocytes and, consequently, compromise their transdifferentiation into osteoblasts and, thus, adequate bone repair. According to our clinical data,(23) indicating an increased TH expression in fracture hematomas of patients with an increased mental stress load, which is further accompanied by a compromised fracture healing and/or increased pain sensitivity, our preclinical data seem to be of high translational value, suggesting strategies to block immigration of TH positive myeloid cells/ neutrophils into the fracture hematoma or their local release of CAs to represent promising future strategies to facilitate fracture healing in patients who are at risk for psychosomatic disorders.

Main collaborators: Prof. Dr. Melanie Haffner-Luntzer & Prof. Dr. Anita Ignatius (Ulm University, Ulm, Germany), Prof. Dr. Florian Gebhard & Prof. Dr. Konrad Schütze (Ulm University Medical Center, Ulm, Germany).

References: 

1. Yehuda R, Seckl J (2011): Minireview: Stress-related psychiatric disorders with low cortisol levels: a metabolic hypothesis. Endocrinology. 152:4496-4503.

2. Gold PW, Goodwin FK, Chrousos GP (1988): Clinical and biochemical manifestations of depression. Relation to the neurobiology of stress (1). The New England journal of medicine. 319:348-353.

3. Kuzminskaite E, Vinkers CH, Elzinga BM, Wardenaar KJ, Giltay EJ, Penninx BWJH (2020): Childhood Trauma and Dysregulation of Multiple Biological Stress Systems in Adulthood: Results from the Netherlands Study of Depression and Anxiety. Psychoneuroendocrinology.104835.

4. Felitti VJ, Anda RF, Nordenberg D, Williamson DF, Spitz AM, Edwards V, et al. (2019): REPRINT OF: Relationship of Childhood Abuse and Household Dysfunction to Many of the Leading Causes of Death in Adults: The Adverse Childhood Experiences (ACE) Study. Am J Prev Med. 56:774-786.

5. Hughes K, Bellis MA, Hardcastle KA, Sethi D, Butchart A, Mikton C, et al. (2017): The effect of multiple adverse childhood experiences on health: a systematic review and meta-analysis. The Lancet Public Health. 2:e356-e366.

6. Maercker A, Augsburger M (2019): Die posttraumatische Belastungsstörung.  Traumafolgestörungen: Springer, pp 13-45.

7. Steil R, Rosner R (2009): Posttraumatische Belastungsstörung bei Kindern und Jugendlichen. In: Maercker A, editor. Posttraumatische Belastungsstörungen. Berlin, Heidelberg: Springer Berlin Heidelberg, pp 321-343.

8. Gebara MA, Shea ML, Lipsey KL, Teitelbaum SL, Civitelli R, Muller DJ, et al. (2014): Depression, antidepressants, and bone health in older adults: a systematic review. J Am Geriatr Soc. 62:1434-1441.

9. Glaesmer H, Kaiser M, Braehler E, Freyberger HJ, Kuwert P (2012): Posttraumatic stress disorder and its comorbidity with depression and somatisation in the elderly - a German community-based study. Aging Ment Health. 16:403-412.

10. Calarge CA, Butcher BD, Burns TL, Coryell WH, Schlechte JA, Zemel BS (2014): Major depressive disorder and bone mass in adolescents and young adults. J Bone Miner Res. 29:2230-2237.

11. Zong Y, Tang Y, Xue Y, Ding H, Li Z, He D, et al. (2016): Depression is associated with increased incidence of osteoporotic thoracolumbar fracture in postmenopausal women: a prospective study. Eur Spine J. 25:3418-3423.

12. Glaesmer H, Brahler E, Gundel H, Riedel-Heller SG (2011): The association of traumatic experiences and posttraumatic stress disorder with physical morbidity in old age: a German population-based study. Psychosom Med. 73:401-406.

13. Cizza G, Ravn P, Chrousos GP, Gold PW (2001): Depression: a major, unrecognized risk factor for osteoporosis? Trends Endocrinol Metab. 12:198-203.

14. Cizza G, Primma S, Coyle M, Gourgiotis L, Csako G (2010): Depression and Osteoporosis: A Research Synthesis with Meta-Analysis. Horm Metab Res. 42:467-482.

15. Tsai J, Shen J (2017): Exploring the Link Between Posttraumatic Stress Disorder and inflammation-Related Medical Conditions: An Epidemiological Examination. Psychiatr Q.

16. Batty GD, Shipley MJ, Gunnell D, Huxley R, Kivimaki M, Woodward M, et al. (2009): Height, wealth, and health: an overview with new data from three longitudinal studies. Econ Hum Biol. 7:137-152.

17. Reber SO, Langgartner D, Foertsch S, Postolache TT, Brenner LA, Guendel H, et al. (2016): Chronic subordinate colony housing paradigm: A mouse model for mechanisms of PTSD vulnerability, targeted prevention, and treatment—2016 Curt Richter Award Paper. Psychoneuroendocrinology. 74:221-230.

18. Reber S, Birkeneder L, Veenema A, Obermeier F, Falk W, Straub R, et al. (2007): Adrenal insufficiency and colonic inflammation after a novel chronic psycho-social stress paradigm in mice: implications and mechanisms. Endocrinology. 148:670-682.

19. Foertsch S, Haffner-Luntzer M, Kroner J, Gross F, Kaiser K, Erber M, et al. (2017): Chronic psychosocial stress disturbs long-bone growth in adolescent mice. Dis Model Mech. 10:1399-1409.

20. Molinoff PB, Axelrod J (1971): Biochemistry of catecholamines. Annu Rev Biochem. 40:465-500.

21. Heidt T, Sager HB, Courties G, Dutta P, Iwamoto Y, Zaltsman A, et al. (2014): Chronic variable stress activates hematopoietic stem cells. Nature medicine. 20:754.

22. Haffner-Luntzer M, Foertsch S, Fischer V, Prystaz K, Tschaffon M, Mödinger Y, et al. (2019): 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.201819218.

23. Tschaffon-Müller MEA, Kempter E, Steppe L, Kupfer S, Kuhn MR, Gebhard F, et al. (2023): Neutrophil-derived catecholamines mediate negative stress effects on bone. Nat Commun. 14:3262.

24. De Filippo K, Dudeck A, Hasenberg M, Nye E, van Rooijen N, Hartmann K, et al. (2013): Mast cell and macrophage chemokines CXCL1/CXCL2 control the early stage of neutrophil recruitment during tissue inflammation. Blood. 121:4930-4937.