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Med Hypotheses. 2009 Jul;73(1):83-5. doi: 10.1016/j.mehy.2009.01.029. Epub 2009 Mar 10.

Reciprocal roles between caffeine and estrogen on bone via differently regulating cAMP/PKA pathway: the possible mechanism for caffeine-induced osteoporosis in women and estrogen's antagonistic effects.

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State Key Laboratory of Oral Diseases, No.14, 3rd Section, Remin South Road, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China.


Caffeine is consumed by most people in Europe and North America. As a risk factor for osteoporosis, caffeine has been reported to decrease bone mineral density, negatively influence calcium absorption and increase the risk of bone fracture in women. Except for the epidemiological observations and several studies which proved caffeine's unfavorable effects on osteoblast proliferation and impaired ability to form bone, little mechanism is known for the caffeine-induced osteoporosis. Since our unpublished studies showed that the precursor cells of osteoblasts, bone marrow-derived mesenchymal stem cells (BMSCs), were more sensitive than osteoblasts when exposed to the same dose of caffeine. We herein hypothesize that MSCs may be the primary target cells for caffeine-induced osteoporosis. It is well established that increasing cyclic 3',5'-adenosine monophosphate (cAMP) can regulate the expression of key genes involved in bone metabolism, including Cbfa1, PPARgamma, RANKL and OPG. We thereby propose the hypothesis that caffeine, a known inhibitor of cAMP phosphodiesterase, may affect bone metabolism by activating cAMP-dependent protein kinase A (PKA) pathway. In addition, considering the fact observed in epidemiology that caffeine's negative effects on bone only occurred in postmenopausal women and the inverse roles of caffeine and estrogen on bone metabolism, we postulate that caffeine may exert its undesirable influences on bone only in absence or low level of estrogen in vivo and estrogen may antagonize the adverse effect of caffeine on bone. Since several studies have demonstrated that estrogen may have ability to temper the biological effects of cAMP stimulators' roles on bone through cAMP to regulate some important genes' expression in bone metabolism. We assume that estrogen may block cAMP-dependent PKA pathway which is shared by caffeine, to exhibit its antagonistic roles.

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