BONE LOSS (OSTEOPENIA) IN OLD MALE-MICE RESULTS FROM DIMINISHED ACTIVITY AND AVAILABILITY OF TGF-BETA

One of the universal characteristics of the long bones and spines of m iddle-age and older mammals is a loss in bone mass (osteopenia). In hu mans, if this bone loss is severe enough, it results in osteoporosis, a skeletal disorder characterized by a markedly increased incidence of fractures with sequelae that may include pain, loss of mobility, and in the event of hip fracture, even death within a relatively few month s of injury. An important contributing factor to the development of os teopororsis appears to be a diminution in the number and activity of o steoblasts responsible for synthesizing new bone matrix. The findings in the present and other similar studies suggest that this reduction i n osteoblast number and activity is due to an age-related diminution i n the size and osteogenic potential of the bone marrow osteoblast prog enitor cell (OPC or CFU-f) compartment. We previously postulated that these regressive changes in the OPC/CFU-f compartment occurred in old animals because of a reduction in the amount and/or activity of TGF-be ta 1, an autocrine growth factor important in the promotion of OPVCFU- F proliferation and differentiation. In support of this hypothesis, we now report that (1) the osteogenic capacity of the bone marrow of 24- month-old BALB/c mice, as assessed in vivo, is markedly reduced relati ve to that of 3-4-month-old animals, (2) that the matrix of the long b ones of old mice contains significantly less TGF-beta than that of you ng mice, (3) that OPC's/CFU-f's isolated from old mice produce less TC F-beta in vitro than those recovered from young mice, and (4) that OPC 's/CFU-f's from old mice express significantly more TGF-beta receptor (Types I, II, and III) than those of young animals and that such cells are more responsive in vitro to exogenous recombinant TGF-beta 1. We also find that colony number and proliferative activity of OPC's/CFU-f 's of young mice and old mice, respectively, are significantly reduced when incubated in the presence of neutralizing TGF-beta 1 antibody. C ollectively, these data are consistent with the hypothesis that in old male mice the reduction in the synthesis and, perhaps, availability f rom the bone matrix of TGF-beta 1 contributes to a diminution in the s ize and development potential of the bone marrow osteoprogenitor pool. I. Cell. Biochem. 70:478-488. (C) 1998 Wiley-Liss, Inc.