Placental growth factor mediates mesenchymal cell development, cartilage turnover, and bone remodeling during fracture repair
Christa Maes, … , Roger Bouillon, Geert Carmeliet
Christa Maes, … , Roger Bouillon, Geert Carmeliet
Published May 1, 2006
Citation Information: J Clin Invest. 2006;116(5):1230-1242. https://doi.org/10.1172/JCI26772.
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Research Article Bone biology

Placental growth factor mediates mesenchymal cell development, cartilage turnover, and bone remodeling during fracture repair

Abstract

Current therapies for delayed- or nonunion bone fractures are still largely ineffective. Previous studies indicated that the VEGF homolog placental growth factor (PlGF) has a more significant role in disease than in health. Therefore we investigated the role of PlGF in a model of semistabilized bone fracture healing. Fracture repair in mice lacking PlGF was impaired and characterized by a massive accumulation of cartilage in the callus, reminiscent of delayed- or nonunion fractures. PlGF was required for the early recruitment of inflammatory cells and the vascularization of the fracture wound. Interestingly, however, PlGF also played a role in the subsequent stages of the repair process. Indeed in vivo and in vitro findings indicated that PlGF induced the proliferation and osteogenic differentiation of mesenchymal progenitors and stimulated cartilage turnover by particular MMPs. Later in the process, PlGF was required for the remodeling of the newly formed bone by stimulating osteoclast differentiation. As PlGF expression was increased throughout the process of bone repair and all the important cell types involved expressed its receptor VEGFR-1, the present data suggest that PlGF is required for mediating and coordinating the key aspects of fracture repair. Therefore PlGF may potentially offer therapeutic advantages for fracture repair.

Authors

Christa Maes, Lieve Coenegrachts, Ingrid Stockmans, Evis Daci, Aernout Luttun, Anna Petryk, Rajaram Gopalakrishnan, Karen Moermans, Nico Smets, Catherine M. Verfaillie, Peter Carmeliet, Roger Bouillon, Geert Carmeliet

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Figure 11

Schematic model of the role of PlGF in fracture healing.

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Schematic model of the role of PlGF in fracture healing. (i) Following f...
(i) Following fracture of bone, an inflammatory and angiogenic reaction is initiated, which is dependent on PlGF (see Figures 2 and 3). (ii) Proliferation of mesenchymal progenitor cells is induced in thickened periosteal tissue layers, a process severely affected by PlGF deficiency (see Figure 4). Mesenchymal progenitors bear the capacity to differentiate into chondrocytes (CH) or osteoblasts (OB), forming cartilage or bone, respectively. In the absence of PlGF, osteoblastic differentiation is impaired and chondrocyte differentiation may be favored (see Figures 5 and 6). (iii) Cartilage turnover and its replacement by woven bone through endochondral ossification and (iv) the subsequent remodeling of the new bone are impaired in the absence of PlGF, presumably due to reduced expression of important MMPs and impaired osteoclast functioning, respectively (see Figures 7–10).