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Physiopathology of orphan nuclear receptors

  

Bone is a highly dynamic tissue, displaying during the whole life an equilibrium (referred to as bone remodeling) between formation exerted by osteoblasts and resorption exerted by osteoclasts. This equilibrium is tightly controlled by various factors among which estrogens are instrumental. This is particularly illustrated after menopause in women, when the cessation of ovarian functions leads to a dramatic fall in the levels of circulating estrogens, resulting in bone fragilisation (osteoporosis), due to enhanced resorption by osteoclasts, not compensated for by an equivalent rise in osteoblast activity. Post-menopause osteoporosis can be reduced by hormone replacement therapies, which aim at restoring the pre-menopause levels of circulating estrogens. However, these treatments have been associated with an increased breast cancer risk in various epidemiological studies. Although controversial, these data resulted in a decreased prescription of hormone replacement therapies, thus leaving the problem of osteoporosis unsolved. Furthermore aging also results in bone fragilisation mainly due to decreased bone formation by osteoblasts. Due to the global aging of the world population (particularly in the Western countries), osteoporosis (including post-menopause osteoporosis) now constitutes a major health problem.

JMV5The goal of our team is to propose a new target on which innovative therapies could be designed against osteoporosis, and that would be free of negative side-effects on cancer, in particular those of the breast. We focus our activities on the Estrogen-receptor related receptor alpha (ERRalpha) which is a transcription factor closely related to the Estrogen Receptor, but not modulated by these hormones. Our current work shows that the absence of ERRalpha in mouse models protects the animals against the bone loss induced by aging or by ovariectomy (mimicking the effects of menopause in mice). This is due to the capacity of ERRalpha to reduce at least two steps of the osteoblast differentiation pathway: in the absence of the receptor pre-osteoblasts are more prone to differentiate as well as to mineralize their environment.

We are also studying the effects of the receptor on cancer cells. Epidemiological studies have shown that a high expression of ERRalpha is correlated to a poor prognosis and elevated metastatic capacities in various tumor types, including those of the breast. On the basis, our current work shows that inhibiting ERRalpha in cellular models as well as in vivo results in decreased cell migration capacities through molecular and cellular mechanisms that are currently under investigation in our team.

Given the potential of ERRalpha as a target for the development of new therapies, our team also studies the general molecular mechanisms through which the receptor transcriptionally regulates the expression of its target genes.

Altogether our results strongly suggest that reducing the expression and/or activity of ERRalpha should be beneficial against bone loss induced by aging and/or menopause, while not displaying any negative side effect on cancer. Moreover, ERRalpha could also constitute a target against which to design inhibitors that could reduce cell migration capacities, thus the potential of tumors to establish metastasis.

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