As a model for examining the development of subchondral bone, we are examining the joints of mice who are osteopetrotic (op/op mice). In osteoporosis, reduced osteoclast formation prevents bone resorption, leading to a net overgrowth of bone. The op/op mouse is osteopetrotic due to an alteration in the CSF-1 (Colony Stimulating Factor-1) gene. This mutation, the insertion of a thymidine 262 base pairs downstream of the ATG start codon in the CSF-1 gene, leads to a frame shift and the introduction of a premature stop codon. As a result, the mutated gene encodes a truncated protein product of about 60 amino acids, which lacks biological activity. CSF-1 normally stimulates the differentiation of osteoclast progenitors into osteoclasts and may also regulate mature osteoclasts. In the op/op mouse, the lack of CSF-1 leads to osteopetrosis due to a marked reduction in osteoclast numbers; the bone produced cannot be resorbed. Studies in Dr. Stanley's lab and elsewhere have shown that either spontaneous aging or injections of human recombinant CSF-1 into op mice from 3 days of life, is capable of reverting diaphyseal bone (i.e. bone in the shaft of the femur) to more normal histology, but subchondral bone remains petrotic. Drs. Hamerman and Stanley will examine the macrophage and osteoclast populations over time in the subchondral and diaphyseal bone in aging and CSF-1 treated mice. In addition, the histologic state of the overlying articular cartilage will be examined to determine if petrotic subchondral bone is associated with degeneration of the overlying articular cartilage.

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