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Figure 1. Proposed role for PHEX, MEPE, and the ASARM peptide in mineralization. MEPE and osteoblastic proteases (NEP, ECEL-1/DINE, and cathepsin-D) are markedly up-regulated in murine hyp-osteoblasts that have defective phex (Jo et al., 2000, 2001; Argiro et al., 2001; Bai et al., 2002; Dubois et al., 2002; Guo et al., 2002; Liu et al., 2003). PHEX/phex protects MEPE from cathepsin-B and general protease degradation and prevents release of the ASARM peptide (Guo et al., 2002). Cathepsin-B is also expressed in the osteoblast (Aisa et al., 1996, 2003). Thus, in HYP/hyp, elevated MEPE (with elevated osteoblastic proteases and loss of PHEX protease protection of MEPE) results in elevated levels of protease-resistant MEPE-ASARM peptide. The MEPE-ASARM peptide inhibits mineralization in vivo, and the osteopontin ASARM peptide potently inhibits calcium oxalate crystallization and crystal growth (Rowe et al., 2000, 2004; Hoyer et al., 2001). Also, the salivary statherin ASARM peptide (see Fig. 2) plays a direct biological role in inhibiting spontaneous precipitation of supersaturated salivary calcium and phosphate and maintaining the mineralization dynamics of tooth enamel (Schlesinger and Hay, 1977; Bennick et al., 1981; Raj et al., 1992; Long et al., 1998). Of related interest, the MEPE knockout, as expected, has accelerated mineralization and increased bone density and bone formation (Gowen et al., 2003). Mineral maturity (mineral crystal size and perfection) throughout all anatomic regions of the osteopontin knock-out mouse bone are also significantly increased (Boskey et al., 2002).
