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 4

Impaired periosteal cell proliferation in the callus of PlGF–/– mice.

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Impaired periosteal cell proliferation in the callus ...
(A) Schematic represents a fracture with boxes showing the localization of images of B and F. (B–D) Fracture calluses of WT and PlGF–/– mice at PFD3 stained for BrdU to reveal cell proliferation (brown, nuclei). Asterisks indicate cortical bone; arrowheads denote fracture site. Double arrows show thickness of the periosteal layer. p, periosteum. (B) Low-magnification view localizing the areas shown in C (box 1) and D (box 2). (C) Periosteum on the outer surfaces of the cortex fragments near the fracture site. WT mice showed strongly thickened periosteum containing abundant BrdU-positive cells, whereas PlGF–/– mice exhibited only a thin periosteal layer with scarcely detectable proliferation. (D) Marrow near the fracture site. In WT mice, considerable proliferation was observed internally in the callus (red box), whereas the number of BrdU-stained cells was reduced in PlGF–/– calluses. (E) Periosteal area and proliferation index (BrdU-positive nuclei relative to periosteal area) in WT and PlGF–/– calluses at PFD3 (as in C). Data are mean α SEM. **P < 0.01 (2-sided 2-sample Student’s t test; n = 6–7). (F) Magnified view of the periosteal thickening of WT calluses (PFD3) examined by H&E staining, Sirius red staining, Runx2 in situ hybridization, and osteocalcin immunostaining, showing morphology, collagen fibers, Runx2 expression, and osteocalcin protein, respectively. Scale bars: 200 μm.