DJ-1 promotes angiogenesis and osteogenesis by activating FGF receptor-1 signaling

Abstract

Communication between osteoblasts and endothelial cells is essential for bone fracture repair, but the molecular identities of such communicating factors are not well defined. Here we identify DJ-1 as a novel mediator of the cross-talk between osteoblasts and endothelial cells through an unbiased screening of molecules secreted from human mesenchymal stem cells during osteogenesis. We show that DJ-1 stimulates the differentiation of human mesenchymal stem cells to osteoblasts and that DJ-1 induces angiogenesis in endothelial cells through activation of fibroblast growth factor receptor-1 signalling. In a rodent model of bone fracture repair, extracellular application of DJ-1 enhances bone regeneration in vivo by stimulating the formation of blood vessels and new bones. Both these effects are blocked by antagonizing fibroblast growth factor receptor-1 signalling. These findings uncover previously undefined extracellular roles of DJ-1 to promote angiogenesis and osteogenesis, suggesting DJ-1 may have therapeutic potential to stimulate bone regeneration.

Blood vessel formation and function in bone

“…DJ-1 (PARK7), which was identified as an angiogenic factor secreted from human MSCs, can activate FGFR1-mediated signaling and stimulates both angiogenesis and osteoblast differentiation in vitro. Consistent with these findings, DJ-1 enhances the healing of experimental lesions in a rat model (Kim et al, 2012). Fgf9 heterozygous mutant mice show impaired bone healing, reduced expression of VEGF and VEGFR2 in the lesion, reduced osteoclast recruitment to the callus, and lower MMP9 expression.…”

Bringing new life to damaged bone: The importance of angiogenesis in bone repair and regeneration

“…Kim et al identified DJ-1 as an angiogenic factor produced by human MSC [40], which induces a direct angiogenic response in EC through activation of FGFR1 and regulates angiogenesis indirectly by stimulating VEGF production by osteoblasts. In addition, DJ-1 stimulates the differentiation of MSC and exogenous administration of DJ-1 enhances bone regeneration in a rodent model of bone fracture repair.…”

6-Hydroxydopamine induces secretion of PARK7/DJ-1 via autophagy-based unconventional secretory pathway

“…For example, PARK7 secreted from osteoblasts has been found to promote angiogenesis and osteogenesis [32]. Extracellular deposition of abnormal TTR (transthyretin) protein has been shown to cause familial amyloid polyneuropathy, and secreted PARK7 has been shown to degrade aggregated TTR to protect against the onset of amyloid polyneuropathy [26].…”

“…There have been conflicting reports of both increase [28] and decrease [29] in the amount of PARK7 in cerebrospinal fluid in sporadic PD patients as compared with control groups. Secreted PARK7 plays important physiological and pathophysiological roles which include involvement in anti-oxidative effects [30], extracellular signaling between neighboring neuronal cells [31], angiogenic and osteogenic factors [32], and degradation of aggregated protein [26]. Such findings indicate that PARK7 secretion may be implicated in the etiology and/or progression of diseases such as PD and cancer, possibly making it suitable for use as a biomarker.…”