During osteoporosis bone formation by osteoblasts is reduced and/or bone resorption by osteoclasts is enhanced. Currently, only a few factors have been identified in the regulation of bone integrity by osteoblast-derived osteocytes. In this study, we show that specific disruption of menin, encoded by multiple endocrine neoplasia type 1 (Men1), in osteoblasts and osteocytes caused osteoporosis despite the preservation of osteoblast differentiation and the bone formation rate. Instead, an increase in osteoclast numbers and bone resorption was detected that persisted even when the deletion of Men1 was restricted to osteocytes. We demonstrate that isolated Men1-deficient osteocytes expressed numerous soluble mediators, such as C-X-C motif chemokine 10 (CXCL10), and that CXCL10-mediated osteoclastogenesis was reduced by CXCL10-neutralizing antibodies. Collectively, our data reveal a novel role for Men1 in osteocyte-osteoclast crosstalk by controlling osteoclastogenesis through the action of soluble factors. A role for Men1 in maintaining bone integrity and thereby preventing osteoporosis is proposed. Cell Death and Differentiation (2017) 24, 672-682; doi:10.1038/cdd.2016.165; published online 20 January 2017The maintenance of bone mass is severely affected in osteoporotic patients and other bone disorders and can have multiple etiologies. The complex communication of boneforming osteoblasts, bone-residing osteocytes, and boneresorbing osteoclasts is still not fully understood. Two hallmark studies 1,2 have demonstrated that osteocytes are the major source of the osteoclastogenesis-stimulating factor RANKL and thus key components in the control of bone mass. This property goes beyond their previously suggested function of sensing the mechanical loading of bone. 3 PTH 4 and sclerostin 5 have been reported to stimulate osteocytes to support osteoclastogenesis via a RANKL-dependent pathway. High-mobility group box 1 (HMGB1), which is chemotactic to osteoclasts, is enhanced in apoptotic MLO-Y4 cells; 6 however, there is little information on other factors controlling osteoclast activity by osteoblast-derived osteocytes.The nuclear protein menin encoded by the gene Men1 (multiple endocrine neoplasia type 1) has recently been suggested to control bone mass at higher age through its influence on the differentiation and function of osteoblasts. 7 In vitro studies in cell lines and primary osteoblasts derived from 6-month-old mice showed that menin promotes early osteoblast differentiation in committed cells. Knockdown of Men1 with antisense oligonucleotides lead to enhanced BMP2 signaling [8][9][10] and to facilitated inhibition of the late stage of osteoblast differentiation by potentiating TGFβ-dependent Smad3 signaling. 11,12 Accordingly, reduced bone mass and reduced bone formation due to decreased osteoblast proliferation and differentiation and enhanced apoptosis have been reported using aged osteocalcin-cre mice crossed to Men1 floxed mice that leads to a conditional deletion of menin in the late stage of differentiate...

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