Chronic psychosocial stress disturbs bone homeostasis and fracture healing

Introduction:

Stress-related mental disorders are associated with osteoporosis and increased fracture risk. Furthermore, chronic stress may disturb bone growth, since people with repeated psychological traumatization in childhood are from shorter stature.

Materials and methods:

Here we investigated if bone homeostasis and fracture healing are disturbed by chronic stress using the chronic subordinate colony housing (CSC) paradigm, a mouse model for chronic psychosocial stress. To investigate fracture healing, mice received a femur osteotomy, stabilized by an external fixator. To find out molecular mechanisms disturbing endochondral ossification, an in vitro assay for osteogenic differentiation of chondrogenic differentiated ATDC5 cells was established.

Results:

CSC mice showed a disturbed long bone growth as wells as a delayed fracture healing after femur osteotomy, compared to single-housed control (SHC) mice. Reduced expression of Runx2, VEGF and Sox2 in chondrocytes in the cartilage-to-bone transition zone suggests a disturbed transdifferentiation of chondrocytes into osteoblasts in CSC mice. The expression of tyrosine hydroxylase, the rate limiting enzyme of the catecholamine synthesis, was significantly increased in the intact bone and in the fracture callus of CSC mice, indicating an increased local release of catecholamines. FACS analysis characterized the catecholamine-producing cells as myeloid bone marrow cells. Treatment of ATDC5 cells with conditioned medium of those cells as well as with synthetic catecholamines significantly decreased the expression of transdifferentiation markers.

Discussion:

We hypothesize the locally increased catecholamine synthesis to be responsible for the disturbed endochondral ossification in CSC mice. The reduced transdifferentiation of ATDC5 cells treated with conditioned medium of myeloid bone marrow cells from CSC mice and with synthetic catecholamines in vitro confirms this hypothesis.

Key words:

Psychosocial stress, bone, fracture healing, endochondral ossification

* both last authors contributed equally to the study