Fig. 4.

Integration of UPR signaling cascades in bone cell differentiation. a BMP-2 SMAD1/5/8 signaling and non-canonical WNT signaling promote ER stress and UPR pathway activation. EIF2AK3 activation induces ATF4 which promotes expression of SP7 and interacts with RPS6KA3 to post-transcriptionally regulate COLα1(1) processing. ERN1 splices XBP1 with sXBP1 promoting expression of SP7 and PTH1R. Activated ATF6 and CREB3L1 translocate to the Golgi where they are proteolytically processed to produce their active transcriptional form. In the nucleus, ATF6 promotes BGLAP expression and CREB3L1 promotes COL1A1 expression. CREB3L3 is also activated upon ER stress with its active transcriptional form negatively regulating osteoblast signaling. b TNFRSF11A-TNFSF11 signaling stimulates calcium signaling and ROS production which induce ER stress and UPR activation. ERN1 and EIF2AK3 activation mediates ATF4 and sXBP1 promotion of NFATC1 and other osteoclast-specific genes. ATF4 also mediates CSF1 induced surface expression of TNFRSF11A. Activated CREB3, CREB3L3, and CRELD2 translocate to the Golgi where they are proteolytically processed to produce their active transcriptional form. In the nucleus, CREB3L3 promotes NFATC1 expression and CREB3 promotes expression of other osteoclast-specific genes. Alternatively, CRELD2 negatively regulates osteoclast differentiation via inhibition of ER calcium release. (Abbreviations: EIF2AK3 eukaryotic initiation factor 2 alpha kinase 3, ERN1 ER to nucleus signaling 1, XBP1 X-box-binding protein-1, sXBP1 spliced XBP1, MBTPS1 membrane bound transcription factor peptidase, site 1, MBTPS2 membrane bound transcription factor peptidase, site 2, RUNX2 runt-related transcription factor-2, SP7 Sp7 transcription factor, TGFβ transforming growth factor β, TGFβR TGFβ receptor, MAPK mitogen-activated protein kinase, DLX5 distal-less homeobox 5, BMP bone morphogenic protein, BMPR BMP receptor, AP-1 activator protein 1, LRP5/6 low-density lipoprotein receptor-related protein 5 or 6, FZD frizzled, TCF/LEF T cell factor/lymphoid enhancer factor, GSK3B glycogen synthase kinase 3 beta, FGF fibroblast growth factor, FGFR FGF receptor, IGF1 insulin-like growth factor 1, IGF1R IGF1 receptor, PIK3CA phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha, PLCG phospholipase C gamma, PTH parathyroid hormone, PTH1R PTH1 receptor, PRKACA protein kinase cAMP-activated catalytic subunit alpha, CREB cAMP-response element binding protein, CALM calmodulin, ROR2/RYK receptor tyrosine kinase of the ROR-2 and Ryk families, DAAM1 disheveled associated activator of morphogenesis 1, ATF4 activating transcription factor 4, BGLAP bone gamma-carboxyglutamate protein, SP1 secreted phosphoprotein 1, IBSP integrin binding sialoprotein, COL1A1 collagen type 1 alpha 1 chain, RPS6KA3 ribosomal S6 kinase A3, CREB3L1 cAMP responsive element binding protein 3 like 1, CREB3L3 cAMP responsive element binding protein 3 like 3, CSF1 colony stimulating factor 1, CSF1R CSF1 receptor, TNFRSF11A tumor necrosis factor receptor family member 11A, TNFSF11 tumor necrosis factor soluble factor 11, MITF melanocyte-induced transcription factor, TRAF6 tumor necrosis factor receptor-associated factor 6, MAPK mitogen-activated protein kinase, NFATC1 nuclear factor of activated T cells 1, CEBPA CCAAT enhancer binding protein alpha, AP-1 activator protein 1, TREM2 triggering receptor expressed on myeloid cells 2, OSCAR osteoclast-associated Ig-like receptor, TYROBP transmembrane immune signaling adaptor, FCRG Fc gamma receptor, SYK spleen associated tyrosine kinase, BTK Bruton’s tyrosine kinase, PLCG2 phospholipase C gamma 2, CALM calmodulin, CYBB cytochrome b-245 beta chain, ROS reactive oxygen species, DCSTAMP dendrocyte expressed seven transmembrane protein, OCSTAMP osteoclast stimulatory transmembrane protein, ATP6V0D2 ATPase H+ transporter V0 subunit d2, SH3PXD2A SH3 and PX domains 2A, ITGB3 integrin subunit beta 3, CLCN7 chloride voltage-gated channel 7, OSTM1 osteoclastogenesis associated transmembrane protein1, CTSK cathepsin K, ACP5 tartrate-resistant acid phosphatase 5, VAV3 vav guanine nucleotide exchange factor 3, CA2 carbonic anhydrase 2, MMP9 matrix metallopeptidase 9, CREB3 cAMP responsive element binding protein 3, CRELD2 cystine rich with EGF like domains 2