GPNMB enhances bone regeneration by promoting angiogenesis and osteogenesis: Potential role for tissue engineering bone

Abstract

Bone regeneration is a coordinated process involving the connection between blood vessels and bone cells. Glycoprotein non-metastatic melanoma protein B (GPNMB) is known to be vital in bone formation. However, the effect of GPNMB on bone regeneration and the underlying molecular mechanism are still undefined. Fibroblast growth factor receptor (FGFR)-mediating signaling is pivotal in bone formation and angiogenesis. Therefore, we assessed GPNMB function as a communicating molecule between osteoblasts and angiogenesis, and the possible correlation with FGFR-1 signaling. Recombinant GPNMB dose-dependently increased the differentiation of human bone marrow stromal cells (hBMSCs) into osteoblasts, as well as the mRNA levels of osteoblasts marker alkaline phosphatase (ALP) and osteocalcin (OCN). Furthermore, these increases depended on the activation of FGFR-1 signaling, as pretreatment with FGFR-1 siRNA or its inhibitor SU5402 dramatically dampened GPNMB-induced osteogenesis. Additionally, GPNMB triggered dose-dependently the proliferation and migration of human umbilical vein endothelial cells (hUVECs), FGFR-1 phosphorylation, as well as capillary tube and vessels formation in vitro and in vivo. Blocking FGFR-1 signaling dampened GPNMB-induced angiogenic activity. Following construction of a rodent cranial defect model, scaffolds delivering GPNMB resulted in an evident increase in blood vessels and new bone formation; however, combined delivery of GPNMB and SU5402 abated these increase in defect sites. Taken together, these results suggest that GPNMB stimulates bone regeneration by inducing osteogenesis and angiogenesis via regulating FGFR-1 signaling. Consequently, our findings will clarify a new explanation about how GPNMB induces bone repair, and provide a potential target for bone regeneration therapeutics and bone engineering.

Thermodynamically Controlled Self‐Assembly of Hierarchically Staggered Architecture as an Osteoinductive Alternative to Bone Autografts

“…Bone defect healing is a dynamic progenitor cell‐driven tissue morphogenetic process that requires coordinated osteogenesis and angiogenesis at the repair site . To explore the complex interplay of autocrine and paracrine factors produced by osteoblasts, endothelial cells, and their precursors during bone defect healing, the engineered bone was further characterized for osteogenesis and angiogenesis by staining for related factors produced by osteoblasts and endothelial cells.…”

Synergistic effect of extracellularly supplemented osteopontin and osteocalcin on stem cell proliferation, osteogenic differentiation, and angiogenic properties

“…10,53 Recombinant human OPN protein was purchased from R&D Systems (Minneapolis, MN) and human OC fragment 1 to 49 was purchased from Sigma-Aldrich. Different concentrations of OPN and OC were exogenously applied to the cell culture (0, 0.01, 0.05, 0.1, 0.2, 0.5, 1 µg/mL), based on previous works.…”

“…2 In particular, the scarcity of bone graft donors, as well as the high risk of immunologic rejection and infection limited the clinical use of allografts. 10 Bone extracellular matrix consists of two different components: an organic matrix, constituted by collagen and noncollagenous proteins (NCP), 11, 12 and an inorganic phase, composed mainly by hydroxyapatite crystals. 3 Tissue engineering technologies offer advances to regenerate bone including the development of scaffolds that can release growth factors in a controlled manner, such as bone morphogenetic protein-2 (BMP-2) and basic fibroblast growth factor (bFGF) proteins, 5 having great potential for tissue engineering and regenerative medicine.…”

High levels of FLT3-ligand in bone marrow and peripheral blood of patients with advanced multiple myeloma

“…A previous study associated osteoactivin with promotion of angiogenesis after shedding its ectodomain of the surface of breast cancer cells [26]. Moreover, it has been shown that osteoactivin acts as communicating molecule promoting osteogenesis and angiogenesis [27]. The role of osteoactivin as a potential angiogenic factor in multiple myeloma is still not defined.…”