The effects of colony-stimulating factor-1 (CSF-1) on the development of osteoclasts and their expression of tartrate-resistant acid phosphatase (TRAP) in toothless (tl-osteopetrotic) rats.

The osteopetrotic mutation toothless (tl) in the rat is characterized by a limited number of osteoclasts with reduced amounts and/or activity of tartrate-resistant acid phosphatase (TRAP). Treatment of tl/tl mutants with the cytokine colony-stimulating factor (CSF)-1 increases both osteoclast number and enzyme activity, consistent with a loss-of-function mutation in the CSF-1 gene recently detected in this mutant. We have pursued these observations to demonstrate that there is a dose-dependent increase in osteoclast number, but not to normal levels. Osteoclasts in CSF-1-treated tl/tl mutants are large, have well-developed clear zones and ruffled borders, and secrete TRAP into resorption lacunae. The expression of TRAP mRNA, protein, and enzyme activity per bone appear normal after CSF-1 treatment. However, in contrast to the predominantly apical intracellular distribution in normal osteoclasts, an enrichment of TRAP enzyme activity in osteoclasts of CSF-1-treated tl/tl mutants is observed in the basal part of the cell. Our observations suggest that the CSF-1-treated mutant bones contain an abundance of mature osteoclasts, actively expressing markers for osteoclasts such as TRAP, cathepsin K, and matrix metalloproteinase (MMP)-9. Accumulation of TRAP at the end of the endocytic pathway in mature osteoclasts formed during CSF-1 treatment suggests that the TRAP enzyme has a rapid turnover in these highly active cells and uses a transcytotic pathway.