Abnormalities in bone cell function and endochondral ossification in the osteopetrotic toothless rat.

The toothless (tl) rat is an osteopetrotic mutation whose excess skeletal mass is produced by a defect in its skeletal microenvironment. Its skeletal sclerosis fails to be cured by bone marrow transplantation but is largely reversed by exogenous administration of colony stimulating factor 1 which increases osteoclast neogenesis and resorptive activity. Recent studies have also indicated abnormalities in growth plate cartilage morphology and in osteoblast number and function in the tl rat. The present histomorphometric study examined static and kinetic parameters of bone cell and cartilage function in young (3-5-week-old) animals of tl stock for evidence of tissue level dysfunction. Mineralization of growth plate cartilage in mutants occurred only in the lateral regions of the growth plate, not in the central region, and longitudinal bone growth was significantly reduced (36%-61%) in mutants at the ages examined. Bone volume and trabecular thickness were greater in mutants despite significant reductions in their osteoblast populations and bone formation rates (two to threefold lower). Mutants also showed progressive age- and metaphyseal site-related decreases in osteoblast numbers which, compared to normal littermates, may relate to differences in osteoprogenitor cell pools, osteoblast lifespan, or resorption-derived skeletal growth factors locally available to support and maintain normal osteoblast phenotype. Osteoclast number per millimeter bone perimeter was reduced 96-fold in mutants and showed no age- or metaphyseal site-related changes. This study presents evidence in support of defects in chondrocyte and bone cell function in the tl rat and reveals the specific tissue locations where they occur.