REDUCED BONE-RESORPTION IN TOOTHLESS (OSTEOPETROTIC) RATS - AN ABNORMALITY OF OSTEOBLASTS RELATED TO THEIR INABILITY TO ACTIVATE OSTEOCLASTACTIVITY IN-VITRO

Osteopetrosis is a heterogeneous group of metabolic bone disorders cha racterized by reduced bone resorption, In the toothless (tl) osteopetr otic rat mutation there are few osteoclasts and mutants are not cured by bone marrow transplants, This suggests that the defect(s) in tl rat s is within the skeletal microenvironment and not one of stem cell inc ompetence. Osteoblasts are known to play a role in bone resorption and abnormalities in these cells have been reported in tl rats, We explor ed the ability of osteoblasts from tl rats to activate resorption by n ormal osteoclasts when co-cultured in the presence of 1,25-dihydroxyvi tamin D (1,25(OH)2D), Stimulation with 1,25(OH)2D produced a highly si gnificant response in normal osteoblast co-cultures, but no response w as observed in mutant cultures over a wide dose range, Ligand-binding studies demonstrated no abnormalities in vitamin D receptor (VDR) affi nity, but mutant osteoblasts had reduced VDR numbers, Taken together w ith the demonstrated resistance of these mutants to the hypercalcemic effects of 1,25(OH)2D and parathyroid hormone in vivo, these data impl icate osteoblasts in the pathogenesis of this mutation.