Recombinant TGF-beta 1 stimulates bone marrow osteoprogenitor cell activity and bone matrix synthesis in osteopenic, old male mice

We have previously hypothesized that the osteopenic changes seen in the ske letons of old male BALB/c mice are due to reductions in the availability an d/or synthesis of bone TGF-beta which results in fewer, less osteogenic mar row osteoprogenitor cells (CFU-f, OPCs) and lower levels of bone formation. Among other things, this hypothesis would predict that introducing exogeno us TGF-beta into old mice (growth factor replacement) should stimulate marr ow CFU-f and increase bone formation. In the present study, we have tested this prediction and, indirectly the hypothesis, by injecting human recombin ant TGF-beta 1, i.p., into both young adult (4 month) and old mice (24 mont h). The effects of the growth factor on the skeleton were then assessed by measurements of trabecular bone volume, bone formation, fracture healing, a nd the number, proliferative, apoptotic, and alkaline phosphatase activity of marrow CFU-f/OPCs. Our data show that the introduction of 0.5 or 5.0 ug/ day of TGF-beta 1 into old mice for 20 days 1) increases trabecular bone vo lume, bone formation and the mineral apposition rate, 2) augments fracture healing, 3) increases the number and size of CFU-f colonies, and 4) increas es proliferation and diminishes apoptosis of CFU-f in primary bone marrow c ultures. Importantly, these stimulatory effects of injected growth factor a re apparently age-specific, i.e., they are either not seen in young animals or, if seen, are found at much lower levels. While these observations do n ot exclude other possible mechanisms for the osteopenia of old mice, they p rovide further support for the hypothesis that, with age, diminished TGF-be ta synthesis or availability results in a reduction in the marrow osteoprog enitor pool and bone formation. The findings also demonstrate that the latt er changes can be reversed, at least transiently, by introducing exogenous TGF-beta 1. J. Cell. Biochem. 73:379-389, 1999. (C) 1999 Wiley-Liss, Inc.