Ds. Miao et al., Osteomalacia in Hyp mice is associated with abnormal Phex expression and with altered bone matrix protein expression and deposition, ENDOCRINOL, 142(2), 2001, pp. 926-939
To explore how the loss of Phex function contributes to the pathogenesis of
osteomalacia, we examined the abnormalities of mineralization, Phex, and b
one matrix protein expression occurring in Hyp mice in vivo and in ex vivo
bone marrow cell cultures. The results in vivo show that mineralization was
decreased significantly in Hyp mouse bone. Phex protein was identifiable i
n osteoblasts and osteocytes in wild-type mice, but not in Hyp mice. In Hyp
mice, osteocalcin, bone sialoprotein, and vitronectin expression were down
-regulated, whereas biglycan and fibrillin-1 expression were up-regulated i
n osteocytes and bone matrix relative to those in their wild-type counterpa
rts. Parallel studies ex vivo demonstrated that cells derived from 18-day H
yp mouse bone marrow cell cultures had a 3'-Phex deletion, no Phex protein
expression, decreased alkaline phosphatase activity, collagen deposition, a
nd calcium accumulation, and reduced osteocalcin, bone sialoprotein, and vi
tronectin at both the protein and messenger RNA levels. Furthermore conditi
oned medium from Hyp mouse bone marrow cultures could induce analogous defe
cts in bone marrow cell cultures of wild-type cells. These novel findings i
ndicate that there is an intrinsic osteogenic cell differentiation defect i
n addition to the known hypomineralization of bone in Hyp mice, which may b
e inducible by an autocrine/paracrine secreted factor. These results sugges
t that alterations in the Phex gene may control bone matrix mineralization
indirectly by regulating the synthesis and deposition of bone matrix protei
ns.