Intermittent PTH Administration Stimulates Pre-Osteoblastic Proliferation Without Leading to Enhanced Bone Formation in Osteoclast-Less c-fos−/− Mice

Abstract

This study aimed to investigate the behavior and ultrastructure of osteoblastic cells after intermittent PTH treatment and attempted to elucidate the role of osteoclasts on the mediation of PTH-driven bone anabolism. After administering PTH intermittently to wildtype and c-fos(-/-) mice, immunohistochemical, histomorphometrical, ultrastructural, and statistical examinations were performed. Structural and kinetic parameters related to bone formation were increased in PTH-treated wildtype mice, whereas in the osteoclast-deficient c-fos(-/-) mice, there were no significant differences between groups. In wildtype and knockout mice, PTH administration led to significant increases in the number of cells double-positive for alkaline phosphatase and BrdU, suggesting active pre-osteoblastic proliferation. Ultrastructural examinations showed two major pre-osteoblastic subtypes: one rich in endoplasmic reticulum (ER), the hypER cell, and other with fewer and dispersed ER, the misER cell. The latter constituted the most abundant preosteoblastic phenotype after PTH administration in the wildtype mice. In c-fos(-/-) mice, misER cells were present on the bone surfaces but did not seem to be actively producing bone matrix. Several misER cells were shown to be positive for EphB4 and were eventually seen rather close to osteoclasts in the PTH-administered wildtype mice. We concluded that the absence of osteoclasts in c-fos(-/-) mice might hinder PTH-driven bone anabolism and that osteoclastic presence may be necessary for full osteoblastic differentiation and enhanced bone formation seen after intermittent PTH administration.