NEONATAL CHANGES OF OSTEOCLASTS IN OSTEOPETROSIS (OP OP) MICE DEFECTIVE IN PRODUCTION OF FUNCTIONAL MACROPHAGE-COLONY-STIMULATING FACTOR (M-CSF) PROTEIN AND EFFECTS OF M-CSF ON OSTEOCLAST DEVELOPMENT AND DIFFERENTIATION/

In mice homozygous for the osteopetrosis (op) mutation, loss of osteoc lasts in the postnatal period and their development, differentiation, and maturation following daily M-CSF administration in adult life were investigated. Histochemical, immunohistochemical, and ultrastructural approaches, as well as [H-3]thymidine autoradiography, clarified the role of M-CSF on osteoclast development and differentiation. In op/op mice osteoclasts appeared normal at birth. However, osteoclast numbers were reduced within a few days after birth, and osteoclasts were unde tectable by 3-4 days of age. In adult op/op mice there were no multinu clear osteoclasts; however, small numbers of mononuclear cells (so-cal led 'preosteoclasts') were observed on the endosteal surface of bone. Those proesteoclasts expressed tartrate-resistant acid phosphatase and showed ultrastructural features of immature osteoclasts. After daily M-CSF administration in op/op mice, osteoclasts developed from the fus ion of preosteoclasts and osteoclast numbers increased to the levels o f normal littermates at 3 days. Autoradiographic analysis with [(3)]th ymidine revealed no labeling in osteoclasts and preoteoclasts. In the mutant mice, M-CSF administration induced numerical increases of monoc ytes, promonocytes, and earlier precursor cells in bone marrow, FR-MP1 2- or, ER-MP58-positive granulocyte/macrophage colony-forming cells (G M-CFCs). Among these macrophage precursors, ER-MP58-positive cells wer e considered proesteoclasts precursors, and possessed marked prolifera tive potential. These data suggest that an ER-MP58-positive cell subpo pulation of GM-CFCs proliferates in response to M-CSF, differentiates into preosteoclasts which fuse with each other to develop into mature osteoclasts.