Overexpression of RANKL implicates IFN-beta-mediated elimination of B-cell precursors in the osteopetrotic bone of microphthalmic mice.

The microphthalmic (mi) mouse possesses a dominant negative mutation in the microphthalmia-associated transcript factor (MITF) transcription factor. These animals are characterized by reduced numbers of peripheral mast and natural killer (NK) cells, are osteopetrotic because of osteoclast reduction and malfunction, lack functional melanocytes, and are deficient for maturing B-cells within the bone marrow. Granulocyte precursor cells, however, are functionally maintained within the mi bone marrow. A central question has been whether the B-cell deficiency of the mi mouse marrow is caused by the absence of an MITF-controlled gene product or because of the compromised, osteopetrotic environment. In this report, we examined mi marrow by performing transcriptional mapping analyses of candidate genes whose products are instrumental for functional osteoclast and B-cell development. Surprisingly, the expression of a subset of such genes including RANKL, stromal-derived factor (SDF-1), B-cell lymphotactin chemokine (BLC), and RANK was dramatically enhanced in the mi marrow. Normal and mutant marrow were also analyzed by subtractive transcript cloning, which identified a number of known and unknown genes with altered transcriptional activity. One such unknown mouse gene possesses a human counterpart that is interferon-beta (IFN-beta) inducible, suggesting the osteopetrotic marrow is enriched for IFN-beta, a cytokine that is known to eliminate B-cell precursors. A model is proposed suggesting excess RANKL sets off a cascade of cytokine production including IFN-beta that leads to the preferential elimination of B-cell precursors in the marrow of osteopetrotic marrow.