Table 1. Summary of the Multiple Stages of Fracture Healing and the Accompanying Expression of Signaling Molecules (based on published results from Kon et al., 2001; Cho et al., 2002; Gerstenfeld et al., 2003b; Dimitriou et al., 2005).

Stage of Fracture Repair	Biological Processes	Expression of Signaling Molecules and their Proposed Functions
Inflammation	Hematoma	IL-1, IL-6, and TNF-α play a role in initiating the repair cascade.
	Inflammation	TGF-β, PDGF, and BMP-2 expression increases to initiate callus formation.
	Recruitment of mesenchymal stem cells	GDF-8 is restricted to day 1, suggesting its role in controlling cellular proliferation.
Cartilage Formation and Periosteal Response	Chondrogenesis and endochondral ossification begins	TGF-β2, -β3, and GDF-5 peak due to their involvement in chondrogenesis and endochondral bone formation.
	Cell proliferation in intramembranous ossification	BMP-5 and -6 rise.
	Vascular in-growth	Angiopoietins and VEGFs are induced to stimulate vascular in growth from vessels in the periosteum.
	Neo-angiogenesis
Cartilage Resorption and Primary Bone Formation	Phase of most active osteogenesis	TNF-α rises in association with mineralized cartilage resorption. This promotes the recruitment of mesenchymal stem cells and induces apoptosis of hypertrophic chondrocytes.
	Bone cell recruitment and woven bone formation	RANKL and MCSF rise in association with mineralized cartilage resorption.
	Chondrocyte apoptosis and matrix proteolysis
	Osteoclast recruitment and cartilage resorption	BMP-3, -4, -7, and -8 rise in association with the resorption of calcified cartilage. They promote recruitment of cells in the osteoblastic lineage.
	Neo-angiogenesis	BMP-5 and -6 remain high during this stage, suggesting a regulatory effect on both intramembranous and endochondral ossification.
		VEGFs are up-regulated to stimulate neo-angiogenesis.
Secondary Bone Formation and Remodeling	Bone remodeling coupled with osteoblast activity	IL-1 and IL-6 rise again in association with bone remodeling, whereas RANKL and MCSF display diminished levels.
	Establishment of marrow	Diminished expression of members of the TGF-β superfamily.