The promotion of bone healing by progranulin, a downstream molecule of BMP-2, through interacting with TNF/TNFR signaling

Endochondral ossification plays a key role in the bone healing process, which requires normal cartilage callus formation. Progranulin (PGRN) growth factor is known to enhance chondrocyte differentiation and endochondral ossification during development, yet whether PGRN also plays a role in bone regeneration remains unknown. In this study we established surgically-induced bone defect and ectopic bone formation models based on genetically-modified mice. Thereafter, the bone healing process of those mice was analyzed through radiological assays including X-ray and micro CT, and morphological analysis including histology and immunohistochemistry. PGRN deficiency delayed bone healing, while recombinant PGRN enhanced bone regeneration. Moreover, PGRN was required for BMP-2 induction of osteoblastogenesis and ectopic bone formation. Furthermore, the role of PGRN in bone repair was mediated, at least in part, through interacting with TNF-α signaling pathway. PGRN-mediated bone formation depends on TNFR2 but not TNFR1, as PGRN promoted bone regeneration in deficiency of TNFR1 but lost such effect in TNFR2 deficient mice. PGRN blocked TNF-α-induced inflammatory osteoclastogenesis and protected BMP-2-mediated ectopic bone formation in TNF-α transgenic mice. Collectively, PGRN acts as a critical mediator of the bone healing process by constituting an interplay network with BMP-2 and TNF-α signaling, and this represents a potential molecular target for treatment of fractures, especially under inflammatory conditions.