Dr. Ron’s Research Review – May 7, 2014

© 2014

This week’s research review focuses on 2ME2 and osteoporosis.

Postmenopausal osteoporotic bone loss occurs mainly due to cessation of ovarian function, which is associated with estrogen deficiency and secondary hyperparathyroidism. (Cagnetta and Patella 2012) (Stubelius, Andreasson et al. 2011)

A recent study by Japanese researchers was published in the Proceedings of the National Academy of Sciences examined the mechanism of estrogen deficiency causing osteoporosis. Bone-resorbing osteoclasts, estrogen-dependent destabilization of hypoxia-inducible factor 1 alpha (HIF1α), which is unstable in the presence of oxygen, plays a pivotal role in promoting bone loss in estrogen-deficient conditions. Estrogen-dependent osteoprotection requires ER-alpha. 2-methoxyestradiol (2ME2), a HIF1α inhibitor, protected Ovx mice from osteoclast activation and bone loss. (Miyauchi, Sato et al. 2013)

The immune system plays a critical role in the pathophysiology of postmenopausal osteoporosis. Estrogen deficiency induces bone loss and at the same time a mild increase in production of pro-inflammatory cytokines, such as IL-1, IL-6, and TNF- alpha, which promotes osteoclastogenesis in the bone marrow. (Cagnetta and Patella 2012)

Dr. Ron


Articles

The role of the immune system in the physiopathology of osteoporosis

         (Cagnetta and Patella 2012) Download

The close anatomical relationship between the immune system, estrogen deficiency and bone loss has been recognized for centuries but the existence of a functional relationship has emerged only recently. The role of the immune system in the development of senile osteoporosis, which arises primarily through the effects of estrogen deficiency and secondary hyperparathyroidism, is slowly being unraveled. This review focuses the evidence that links immune cells, inflammation, cytokine production and osteoclast formation and their activity. The under standing of the interplay of inflammation and osteoclast can lead to the development of new drugs for prevention and treatment of bone loss.

HIF1alpha is required for osteoclast activation by estrogen deficiency in postmenopausal osteoporosis

         (Miyauchi, Sato et al. 2013) Download

In women, estrogen deficiency after menopause frequently accelerates osteoclastic bone resorption, leading to osteoporosis, the most common skeletal disorder. However, mechanisms underlying osteoporosis resulting from estrogen deficiency remain largely unknown. Here we show that in bone-resorbing osteoclasts, estrogen-dependent destabilization of hypoxia-inducible factor 1 alpha (HIF1alpha), which is unstable in the presence of oxygen, plays a pivotal role in promoting bone loss in estrogen-deficient conditions. In vitro, HIF1alpha was destabilized by estrogen treatment even in hypoxic conditions, and estrogen loss in ovariectomized (Ovx) mice stabilized HIF1alpha in osteoclasts and promoted their activation and subsequent bone loss in vivo. Osteoclast-specific HIF1alpha inactivation antagonized bone loss in Ovx mice and osteoclast-specific estrogen receptor alpha deficient mice, both models of estrogen-deficient osteoporosis. Oral administration of a HIF1alpha inhibitor protected Ovx mice from osteoclast activation and bone loss. Thus, HIF1alpha represents a promising therapeutic target in osteoporosis.


Role of 2-methoxyestradiol as inhibitor of arthritis and osteoporosis in a model of postmenopausal rheumatoid arthritis

         (Stubelius, Andreasson et al. 2011) Download

In postmenopausal rheumatoid arthritis, both the inflammatory disease and estrogen deficiency contribute to the development of osteoporosis. As hormone replacement therapy is no longer an option, we hypothesized that 2-methoxyestradiol (2me2) could be beneficial, and asked if such therapy was associated with effects on reproductive organs. Mice were ovariectomized and arthritis was induced, whereafter mice were administered 2me2, estradiol, or placebo. Clinical and histological scores of arthritis, together with bone mineral density were evaluated. Uteri weight, reactive oxygen species (ROS) from spleen cells, and characterization of cells from joints and lymph nodes were analyzed. In addition, in vivo activation of estrogen response elements (ERE) by 2me2 was evaluated. Treatment with 2me2 and estradiol decreased the frequency and severity of arthritis and preserved bone. Joint destruction was reduced, neutrophils diminished and ROS production decreased. The uterine weight increased upon long-term 2me2 exposure, however short-term exposure did not activate ERE in vivo.

References

Cagnetta, V. and V. Patella (2012). "The role of the immune system in the physiopathology of osteoporosis." Clin Cases Miner Bone Metab 9(2): 85-8. [PMID: 23087716]

Miyauchi, Y., Y. Sato, et al. (2013). "HIF1alpha is required for osteoclast activation by estrogen deficiency in postmenopausal osteoporosis." Proc Natl Acad Sci U S A 110(41): 16568-73. [PMID: 24023068]

Stubelius, A., E. Andreasson, et al. (2011). "Role of 2-methoxyestradiol as inhibitor of arthritis and osteoporosis in a model of postmenopausal rheumatoid arthritis." Clin Immunol 140(1): 37-46. [PMID: 21459677]