BRONJ-related jaw bone is associated with increased Dlx-5 and suppressed osteopontin—implication in the site-specific alteration of angiogenesis and bone turnover by bisphosphonates

Abstract

Objectives Site-specific suppression of bone remodelling has been implicated in bisphosphonate-(BP)-related osteonecrosis of the jaws (BRONJ). Due to the origin of jaw bone from cranial neural crest, osseous differentiation is regulated specifically by the antagonizing BMP-2-downstream-transcription factors Msx-1 and Dlx-5. Osteopontin has been implicated in bone remodelling and angiogenesis. The osteoblast and osteoclast progenitor proliferation mediating Msx-1 has been demonstrated to be suppressed in BRONJ. In vitro BPs were shown to increase Dlx-5 and to suppress osteopontin expression. This study targeted Dlx-5 and osteopontin in BRONJ-related and BP-exposed jaw bone compared with healthy jaw bone samples at protein-and messenger RNA (mRNA) level, since increased Dlx-5 and suppressed osteopontin might account for impaired bone turnover in BRONJ. Materials and methods Fifteen BRONJ-exposed, 15 BPexposed and 20 healthy jaw bone samples were processed for real-time reverse transcription polymerase chain reaction (RT-PCR) and for immunohistochemistry. Targeting Dlx-5, osteopontin and glyceraldehyde 3-phosphate dehydrogenase mRNA was extracted, quantified by the LabChip-method, followed by quantitative RT-PCR. For immunohistochemistry, an autostaining-based alkaline phosphatase antialkaline phosphatase (APAPP) staining kit was used. Semiquantitative assessment was performed measuring the ratio of stained cells/ total number of cells (labelling index, Bonferroni adjustment). Results The labelling index was significant decreased for osteopontin (p<0.017) and significantly increased for Dlx-5 (p<0.021) in BRONJ samples. In BRONJ specimens, a significant fivefold decrease in gene expression for osteopontin (p<0.015) and a significant eightfold increase in Dlx-5 expression (p<0.012) were found. Conclusions BRONJ-related suppression of bone turnover is consistent with increased Dlx-5 expression and with suppression of osteopontin. The BP-related impaired BMP-2-Msx-1-Dlx-5 axis might explain the jaw bone specific alteration by BP. Clinical relevance The findings of this study help to explain the restriction of RONJ to craniofacial bones. BRONJ might serve as a model of disease elucidating the specific signal transduction of neural crest cell-derived bone structures in health and disease.

Pilot investigation of the molecular discrimination of human osteoblasts from different bone entities

“…TGFBR1, with a significantly higher expression in iHOBs, is a receptor of the transforming growth factor (TGF) superfamily, including BMPs. These proteins are responsible for immune modulation such as negative bone marrow regulation and progenitor cell proliferation in vitro (Walker, 2000;Yamazaki et al, 2009). Further TGF-b-mediated interaction may play an important role in hematopoietic stem cells hibernation (Yamazaki et al, 2009).…”

“…The function of DLX5 in humans is poorly understood (Samee et al, 2008;Wehrhan et al, 2015). Obviously, DLX 5 activates Runx2 (a key regulator of osteogenesis) and plays a role in the early stages of craniofacial and axial bone development (Samee et al, 2008).…”

The Case of Medication-Related Osteonecrosis of the Jaw Addressed from a Pathogenic Point of View. Innovative Therapeutic Strategies: Focus on the Most Recent Discoveries on Oral Mesenchymal Stem Cell-Derived Exosomes

“…Similar contrasting effects may be understood in light of the fact that N-BPs alter VEGF receptors maturation in endothelial cells, so that the increased expression of VEGF does not exert any effect [74]. In addition, zoledronate treatment may inhibit angiogenesis by reducing the expression of osteopontin (an angiogenesis inducer) in both maxilla and mandible [75]. Finally, N-BPs may also interfere with endothelial differentiation of mesenchymal cells [76].…”

“…On the other hand, Ohlrich et al sh vascular-endothelial growth factor (VEGF) in gingival fibroblast after suggesting the induction of a proangiogenic environment [73]. Similar understood in light of the fact that N-BPs alter VEGF receptors maturat that the increased expression of VEGF does not exert any effect [74] treatment may inhibit angiogenesis by reducing the expression of ost inducer) in both maxilla and mandible [75]. Finally, N-BPs may also differentiation of mesenchymal cells [76].…”

Zoledronate Causes a Systemic Shift of Macrophage Polarization towards M1 In Vivo

“…The pathogenesis of MRONJ is not yet completely understood but it is suggested that BP reduces bone metabolism and turnover—especially in jaw bone [ 1 ]. The different developmental biological origin of jaw bone and extracranial bone is believed to be relevant for the jaw specificity of the disease [ 7 , 8 ]. In addition, immunologic parameters seem to contribute to the pathogenesis of MRONJ.…”