Placental growth factor mediates mesenchymal cell development, cartilage turnover, and bone remodeling during fracture repair
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
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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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 3

Reduced angiogenic reaction to fracture in the absence of PlGF.

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Reduced angiogenic reaction to fracture in the absence of PlGF. (A) CD31...
(A) CD31 immunostaining of WT and PlGF–/– calluses at PFD3 showing reduced accumulation of ECs in PlGF–/– mice. Cortical bone fragments (asterisks) are lined in black. Scale bar: 500 μm. (B) Expression levels of VEGF, VEGFR-1, VEGFR-2, and neuropilin 1 (NRP-1) mRNA during fracture repair in WT and PlGF–/– mice, determined by qRT-PCR. The early upregulation of VEGF and VEGFR-1 expression after fracture (PFD2) was impaired in PlGF–/– mice, and VEGFR-1 mRNA remained significantly lower in mutant calluses compared with WT calluses (PFD5–PFD10). Data are mean α SEM. *P < 0.05, **P < 0.01 versus WT callus (2-sided 2-sample Student’s t test).