ABNORMALITIES IN OSTEOCLAST PRECURSORS AND MARROW ACCESSORY CELLS IN PAGETS-DISEASE

Paget's disease of bone is characterized by increased numbers of abnor mal osteoclasts. To determine if osteoclast precursors were increased or abnormal in this disease, we examined CFU-GM, the committed granulo cyte-macrophage progenitor and the most likely precursor for osteoclas ts. In cultures of unfractionated marrow mononuclear cells, CFU-GM col ony formation was significantly increased in Paget's marrow cultures c ompared to that in normal cells (356 +/- 44 vs. 271 +/- 15/10(5) cells ; P < 0.05). However, when we enriched hematopoietic precursors from P aget's and normal marrow samples using an antibody that recognizes the CD34 antigen present on most hematopoietic precursors, we found that similar numbers of CFU-GM colonies were formed (87 +/- 13/10(4) cells plated vs. 83 +/- 13). Coculture experiments with highly purified hema topoietic precursors (CD34+ cells) and non-hematopoietic marrow access ory cells (CD34- cells) revealed that the growth of Paget's precursors was significantly enhanced above expected levels by normal or Pagetic CD34- cells (P < 0.05). CFU-GM colony formation was also significantl y enhanced when normal CD34+ cells were cocultured with Pagetic, but n ot with normal, CD34- cells. In addition, CFU-GM colony-derived cells from Paget's patients were hyperresponsive to 1,25-dihydroxyvitamin D3 and could form osteoclast-like multinucleated cells with 1,25-dihydro xyvitamin D3 concentrations one tenth of that required for normal mult inucleated formation (10(-11) vs. 10(-10) m). These data suggest that osteoclast precursors may be abnormal in Paget's disease, and other ce lls in the Pagetic marrow microenvironment may further enhance the gro wth and differentiation of these abnormal precursors.