(A) FGF23 regulation in wild-type osteocytes. FGF23 expression in wild-type osteocytes is low due to putative suppressive signals. DMP1 is processed by BMP1/Tolloid-like metalloproteinases to create N- and C-terminal fragments. The model proposes that the C terminus of DMP1 suppresses FGF23 through its binding to PHEX via the ASARM motif and to integrins via the RGD site as well as facilitates mineralization of matrix. In addition, DMP1 is known to have direct transcriptional activities. Putative chondrocyte-derived and unknown systemic factors also suppress FGF23 as described in the text. In addition, FGF23 undergoes posttranslational processing to inactive N- and C-terminal fragments by yet-to-be defined subtilisin-like proprotein convertases (SPCs). (B) Potential mutations and pathways leading to increased FGF23 production. DMP1 and PHEX mutations may indirectly regulate FGF23 promoter activity through the accumulation in the extracellular matrix of an unknown FGF23-stimulating factor or through direct effects on osteocyte function. Loss of PHEX or DMP1 might also permit integrin interactions with FGFRs, leading to FGFR-mediated increases in FGF23 production. Other phosphaturic factors, such as sFRPs (by interfering with DMP1 processing), FGF7 (through activation of FGRs), and MEPE (through competition with DMP1 for PHEX binding [not shown]) may stimulate FGF23 through common pathways. In addition, known mutations of FGF23 that prevent degradation as well as theoretical mutations in SPCs that degrade FGF23 and/or indirectly modulate DMP1 processing by BMP1 are shown.