Abstract
Osteomodulin (OMD), a member of the small leucine-rich proteoglycan family, distributes in mineralized tissues and is positively regulated by bone morphogenetic protein 2 (BMP2). However, the exact function of OMD during mineralization and its association with BMP2 remain poorly understood. Herein, the expression pattern of OMD during osteogenesis was investigated in human dental pulp stem cells. Silencing OMD gene significantly suppressed the alkaline phosphatase activity, mineralized nodule formation and osteogenesis-associated gene transcription. Besides, OMD could enhance BMP2-induced expression of SP7 and RUNX2 with concentration dependence in vitro. Rat mandibular bone defect model revealed that scaffolds injected with the combination of OMD and suboptimal BMP2 exhibited more mature and abundant mineralized bone than that treated with OMD or suboptimal BMP2 alone. Mechanistically, OMD could bind to BMP2 via its terminal leucine-rich repeats and formed complexes with BMP2 and its membrane receptors, thus promoting BMP/SMAD signal transduction. In addition, OMD was a putative target gene of SMAD4, which plays a pivotal role in this pathway. Collectively, these data elucidate that OMD may act as a positive coordinator in osteogenesis through BMP2/SMADs signaling.
Highlights
Oral and maxillofacial bone defects caused by congenital disease, cancer, trauma, infection and other reasons seriously affect the quality of life[1,2]
The mRNA level of OMD significantly increased in the early period of osteogenesis, peaked on day 7 showing about 40-fold upregulation compared with that in growth medium (GM), and maintained this level for about one week, before gradually decreased in the late period of osteogenesis (Fig. 1A)
Though continuously increased level of OMD protein in cells cultured in GM was detected on day 1, 3, 7, more evident increase was shown in osteogenic differentiation medium (OM) during the same period (Fig. 1C)
Summary
Oral and maxillofacial bone defects caused by congenital disease, cancer, trauma, infection and other reasons seriously affect the quality of life[1,2]. BMP2, a leading bone graft substitute, has been associated with an increasing side effect profile because of supraphysiologic dosage[6]. In osseous components modulate the bioactivities of growth factors and cytokines thereby regulating the nature, intensity, and duration of signaling cascades within cells[8], and are likely to be promising in bone bioengineering field. The pericellular localization of SLRPs, along with their multivalent binding abilities, allow for cell–matrix interactions by directly interfering with cell surface receptors and matrix molecules such as cytokines, chemokines and growth factors, leading to modulation of cellular functions[10]. SLRPs take specific roles designated during all phases of bone formation, including cellular growth, organic matrix assembly, mineral deposition, and remodeling[11]. For instance, has been confirmed as a modulator of the Wnt
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