Pleiotrophin/Osteoblast-stimulating factor 1: dissecting its diverse functions in bone formation.

OSF-1, more commonly known as pleiotrophin (PTN) or heparin-binding growth-associated molecule (HB-GAM), belongs to a new family of secreted HB proteins, which are structurally unrelated to any other growth factor family. The aims of this study were to dissect the diverse functions of PTN in bone formation. The study showed that PTN was synthesized by osteoblasts at an early stage of osteogenic differentiation and was present at sites of new bone formation, where PTN was stored in the new bone matrix. Low concentrations (10 pg/ml) of PTN stimulated osteogenic differentiation of mouse bone marrow cells and had a modest effect on their proliferation, whereas higher concentrations (ng/ml) had no effect. However, PTN did not have the osteoinductive potential of bone morphogenetic proteins (BMPs) because it failed to convert C2C12 cells, a premyoblastic cell line, to the osteogenic phenotype, whereas recombinant human BMP-2 (rhBMP-2) was able to do so. When PTN was present together with rhBMP-2 during the osteoinductive phase, PTN inhibited the BMP-mediated osteoinduction in C2C12 cells at concentrations between 0.05 pg/ml and 100 ng/ml. However, when added after osteoinduction had been achieved, PTN enhanced further osteogenic differentiation. An unusual effect of PTN (50 ng/ml) was the induction of type I collagen synthesis by chondrocytes in organ cultures of chick nasal cartilage and rat growth plates. Thus, PTN had multiple effects on bone formation and the effects were dependent on the concentration of PTN and the timing of its presence. To explain these multiple effects, we propose that PTN is an accessory signaling molecule, which is involved in a variety of processes in bone formation. PTN enhances or inhibits primary responses depending on the prevailing concentrations, the primary stimulus, and the availability of appropriate receptors.