Posritong, SumanaHong, Jung MinEleniste, Pierre P.McIntyre, Patrick W.Wu, Jennifer L.Himes, Evan R.Patel, VrutiKacena, Melissa A.Bruzzaniti, Angela2020-01-062020-01-062018-10-15Posritong, S., Hong, J. M., Eleniste, P. P., McIntyre, P. W., Wu, J. L., Himes, E. R., … Bruzzaniti, A. (2018). Pyk2 deficiency potentiates osteoblast differentiation and mineralizing activity in response to estrogen or raloxifene. Molecular and cellular endocrinology, 474, 35–47. doi:10.1016/j.mce.2018.02.005https://hdl.handle.net/1805/21740Bone remodeling is controlled by the actions of bone-degrading osteoclasts and bone-forming osteoblasts (OBs). Aging and loss of estrogen after menopause affects bone mass and quality. Estrogen therapy, including selective estrogen receptor modulators (SERMs), can prevent bone loss and increase bone mineral density in post-menopausal women. Although investigations of the effects of estrogen on osteoclast activity are well advanced, the mechanism of action of estrogen on OBs is still unclear. The proline-rich tyrosine kinase 2 (Pyk2) is important for bone formation and female mice lacking Pyk2 (Pyk2-KO) exhibit elevated bone mass, increased bone formation rate and reduced osteoclast activity. Therefore, in the current study, we examined the role of estrogen signaling on the mechanism of action of Pyk2 in OBs. As expected, Pyk2-KO OBs showed significantly higher proliferation, matrix formation, and mineralization than WT OBs. In addition we found that Pyk2-KO OBs cultured in the presence of either 17β-estradiol (E2) or raloxifene, a SERM used for the treatment of post-menopausal osteoporosis, showed a further robust increase in alkaline phosphatase (ALP) activity and mineralization. We examined the possible mechanism of action and found that Pyk2 deletion promotes the proteasome-mediated degradation of estrogen receptor α (ERα), but not estrogen receptor β (ERβ). As a consequence, E2 signaling via ERβ was enhanced in Pyk2-KO OBs. In addition, we found that Pyk2 deletion and E2 stimulation had an additive effect on ERK phosphorylation, which is known to stimulate cell differentiation and survival. Our findings suggest that in the absence of Pyk2, estrogen exerts an osteogenic effect on OBs through altered ERα and ERβ signaling. Thus, targeting Pyk2, in combination with estrogen or raloxifene, may be a novel strategy for the prevention and/or treatment of bone loss diseases.en-USPublisher PolicyBone formationEstrogen receptorMineralizationOsteoblastPyk2SERMsArticle