Abstract:Craniosynostosis is a significant disorder affecting 1 in 2500 live births worldwide. Although a large body of work has focused on dural regulation and the contributions of molecular mediators such as fibroblast growth factor, bone morphogenetic protein, and transforming growth factor β, minimal attention has been directed toward osteoclast function in cranial suture biology. Receptor activator of nuclear factor κB (RANK) is an essential mediator of osteoclastogenesis and osteoclast activation. In this study, … Show more
“…Expression of Acp5 and Tnfrsf11a were significantly reduced in Bsp −/− vs. WT mouse calvaria at 14 dpn, with a similar trend at 26 dpn, and the same non-significant trend in Ctsk mRNA (Supplementary Figure 1C). Overall, involvement of craniosynostosis genes in the suture alterations in Bsp −/− mice could not be ruled in or out, however reductions in osteoclast markers suggests reduced osteoclast activity may contribute to decreased suture widths (Beederman et al, 2014; Lee et al, 2011). …”
Bone sialoprotein (BSP) is a multifunctional extracellular matrix protein found in mineralized tissues, including bone, cartilage, tooth root cementum (both acellular and cellular types), and dentin. In order to define the role BSP plays in the process of biomineralization of these tissues, we analyzed cementogenesis, dentinogenesis, and osteogenesis (intramembranous and endochondral) in craniofacial bone in Bsp null mice and wild-type (WT) controls over a developmental period (1-60 days post natal; dpn) by histology, immunohistochemistry, undecalcified histochemistry, microcomputed tomography (microCT), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and quantitative PCR (qPCR). Regions of intramembranous ossification in the alveolus, mandible, and calvaria presented delayed mineralization and osteoid accumulation, assessed by von Kossa and Goldner's trichrome stains at 1 and 14 dpn. Moreover, Bsp−/− mice featured increased cranial suture size at the early time point, 1 dpn. Immunostaining and PCR demonstrated that osteoblast markers, osterix, alkaline phosphatase, and osteopontin were unchanged in Bsp null mandibles compared to WT. Bsp−/− mouse molars featured a lack of functional acellular cementum formation by histology, SEM, and TEM, and subsequent loss of Sharpey's collagen fiber insertion into the tooth root structure. Bsp−/− mouse alveolar and mandibular bone featured equivalent or fewer osteoclasts at early ages (1 and 14 dpn), however, increased RANKL immunostaining and mRNA, and significantly increased number of osteoclast-like cells (2-5 fold) were found at later ages (26 and 60 dpn), corresponding to periodontal breakdown and severe alveolar bone resorption observed following molar teeth entering occlusion. Dentin formation was unperturbed in Bsp−/− mouse molars, with no delay in mineralization, no alteration in dentin dimensions, and no differences in odontoblast markers analyzed. No defects were identified in endochondral ossification in the cranial base, and craniofacial morphology was unaffected in Bsp−/− mice. These analyses confirm a critical role for BSP in processes of cementogenesis and intramembranous ossification of craniofacial bone, whereas endochondral ossification in the cranial base was minimally affected and dentinogenesis was normal in Bsp−/− molar teeth. Dissimilar effects of loss of BSP on mineralization of dental and craniofacial tissues suggest local differences in the role of BSP and/or yet to be defined interactions with site-specific factors.
“…Expression of Acp5 and Tnfrsf11a were significantly reduced in Bsp −/− vs. WT mouse calvaria at 14 dpn, with a similar trend at 26 dpn, and the same non-significant trend in Ctsk mRNA (Supplementary Figure 1C). Overall, involvement of craniosynostosis genes in the suture alterations in Bsp −/− mice could not be ruled in or out, however reductions in osteoclast markers suggests reduced osteoclast activity may contribute to decreased suture widths (Beederman et al, 2014; Lee et al, 2011). …”
Bone sialoprotein (BSP) is a multifunctional extracellular matrix protein found in mineralized tissues, including bone, cartilage, tooth root cementum (both acellular and cellular types), and dentin. In order to define the role BSP plays in the process of biomineralization of these tissues, we analyzed cementogenesis, dentinogenesis, and osteogenesis (intramembranous and endochondral) in craniofacial bone in Bsp null mice and wild-type (WT) controls over a developmental period (1-60 days post natal; dpn) by histology, immunohistochemistry, undecalcified histochemistry, microcomputed tomography (microCT), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and quantitative PCR (qPCR). Regions of intramembranous ossification in the alveolus, mandible, and calvaria presented delayed mineralization and osteoid accumulation, assessed by von Kossa and Goldner's trichrome stains at 1 and 14 dpn. Moreover, Bsp−/− mice featured increased cranial suture size at the early time point, 1 dpn. Immunostaining and PCR demonstrated that osteoblast markers, osterix, alkaline phosphatase, and osteopontin were unchanged in Bsp null mandibles compared to WT. Bsp−/− mouse molars featured a lack of functional acellular cementum formation by histology, SEM, and TEM, and subsequent loss of Sharpey's collagen fiber insertion into the tooth root structure. Bsp−/− mouse alveolar and mandibular bone featured equivalent or fewer osteoclasts at early ages (1 and 14 dpn), however, increased RANKL immunostaining and mRNA, and significantly increased number of osteoclast-like cells (2-5 fold) were found at later ages (26 and 60 dpn), corresponding to periodontal breakdown and severe alveolar bone resorption observed following molar teeth entering occlusion. Dentin formation was unperturbed in Bsp−/− mouse molars, with no delay in mineralization, no alteration in dentin dimensions, and no differences in odontoblast markers analyzed. No defects were identified in endochondral ossification in the cranial base, and craniofacial morphology was unaffected in Bsp−/− mice. These analyses confirm a critical role for BSP in processes of cementogenesis and intramembranous ossification of craniofacial bone, whereas endochondral ossification in the cranial base was minimally affected and dentinogenesis was normal in Bsp−/− molar teeth. Dissimilar effects of loss of BSP on mineralization of dental and craniofacial tissues suggest local differences in the role of BSP and/or yet to be defined interactions with site-specific factors.
“…Although they are important for normal maintenance of bone, the function of osteoclasts in cranial suture biology has not been thoroughly investigated. Lee and Spiguel et al found that if RANK expression is knocked down using si-RNA, bone density is increased in a murine, explanted cranial suture model (7). Thus, perturbation in the RANK-RANKL-OPG axis affects murine cranial suture fusion, implicating a role for osteoclasts in cranial suture biology.…”
Section: Discussionmentioning
confidence: 99%
“…Osteoprotegrin (OPG) is a soluble inhibitor of RANK, and confers osteoclast apoptosis (5,6). Our laboratory has shown that suture fusion is correlated with a downregulation of RANK expression (7). This temporospatial relationship was shown in both murine and human suture samples.…”
Section: Introductionmentioning
confidence: 99%
“…Of major interest, OPG protein expression was found to be significantly higher in fused human suture samples compared to nonfused internal controls from craniosynostotic patients (8). Furthermore, blockade of RANK signaling via siRNA technology in murine cranial suture explants produced osseous deposition within the suture fronts, further implicating this pathway in suture homeostasis (7). …”
“…3). 32 Specifically, sentinel work characterized a temporospatial relationship between RANK protein expression and physiologic cranial suture closure in a murine model. Further delineation of osteoclastic modulators through proteomic and candidate gene approaches may spawn the development of animal models for the investigation of nonsyndromic craniosynostosis, as well as molecular-targeted therapies to treat the clinical disease.Figure 3Model for RANK function in cranial suture biology.…”
The normal growth and development of the skull is a tightly regulated process that occurs along the osteogenic interfaces of the cranial sutures. Here, the borders of the calvarial bones and neighboring tissues above and below, function as a complex. Through coordinated remodeling efforts of bone deposition and resorption, the cranial sutures maintain a state of patency from infancy through early adulthood as the skull continues to grow and accommodate the developing brain's demands for expansion. However, when this delicate balance is disturbed, a number of pathologic conditions ensue; and if left uncorrected, may result in visual and neurocognitive impairments. A prime example includes craniosynostosis, or premature fusion of one or more cranial and/or facial suture(s). At the present time, the only therapeutic measure for craniosynostosis is surgical correction by cranial vault reconstruction. However, elegant studies performed over the past decade have identified several genes critical for the maintenance of suture patency and induction of suture fusion. Such deeper understandings of the pathogenesis and molecular mechanisms that regulate suture biology may provide necessary insights toward the development of non-surgical therapeutic alternatives for patients with cranial suture defects. In this review, we discuss the intricate cellular and molecular interplay that exists within the suture among its three major components: dura mater, osteoblastic related molecular pathways and osteoclastic related molecular pathways.
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