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Contextual Regulation of Skeletal Physiology by Notch Signaling

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Contextual Regulation of Skeletal Physiology by Notch Signaling Current Osteoporosis Reports (2019) 17:217–225 https://doi.org/10.1007/s11914-019-00516-y SKELETAL DEVELOPMENT (R MARCUCIO AND J FENG, SECTION EDITORS) Contextual Regulation of Skeletal Physiology by Notch Signaling Daniel W. Youngstrom1 & Kurt D. Hankenson1 Published online: 8 May 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Purpose of Review This article reviews the past 2 years of research on Notch signaling as it relates to bone physiology, with the goal of reconciling seemingly discrepant findings and identifying fruitful areas of potential future research. Recent Findings Conditional animal models and high-throughput omics have contributed to a greater understanding of the context-dependent role of Notch signaling in bone. However, significant gaps remain in our understanding of how spatiotemporal context and epigenetic state dictate downstream Notch phenotypes. Summary Biphasic activation of Notch signaling orchestrates progression of mesenchymal progenitor cells through the osteo- blast lineage, but there is a limited understanding of ligand- and receptor-specific functions. Paracrine Notch signaling through non-osteoblastic cell types contributes additional layers of complexity, and we anticipate impactful future work related to the integration of these cell types and signaling mechanisms. Keywords Notchsignaling .Jagged-1 .Bonebiology .Musculoskeletalmetabolism .Mesenchymalprogenitorcells .Osteoblasts Introduction [2], signal transduction [3], and skeletal disease [4]. In mammals, the Notch family consists of five ligands Low bone mass and bone trauma impose major public health (Jagged-1 and Jagged-2, Delta-like 1, 3, and 4) and four burdens worldwide, and there is a significant interest in iden- single-pass transmembrane receptors (Notch1–4). Active tifying druggable pathways implicated in bone metabolism. binding between ligand and receptor in trans results in Notch, a signaling pathway that regulates a diverse set of proteolytic cleavage of the Notch receptor orchestrated by developmental functions in metazoa, is one such pathway. the γ-secretase complex (with catalytic subunits However, the function of Notch signaling in bone remains presenilin-1/2), liberating the intracellular domain controversial and incompletely understood, in part due to its (NICD) [5, 6]. The NICD then undergoes nuclear translo- high degree of temporal and contextual specificity. cation and, together with coactivator Maml1–3(dominant In October 1918, Otto L. Mohr discovered “serrated or negative mastermind-like 1–3), activates the otherwise in- notched” wing boundary mutations in Drosophila hibitory Rbpj (recombining binding protein suppressor of melanogaster, caused by a novel hemi/homozygous-lethal hairless), also known as CSL, to induce transcription of mutation in what we now know as the Notch pathway [1]. canonical Notch target genes [7, 8]. Classically, these One hundred years later, Notch signaling remains an allur- genes include the Hes and Hey families of bHLH transcrip- ing subject of evolutionary biology and has been exten- tion factors, named from their homology to Drosophila sively reviewed in the contexts of vertebrate development hairy and enhancer-of-split [9]. As with many tissues, Notch signaling is indispensible in proper patterning of the skeleton [10]. This article is part of the Topical Collection on Skeletal Development The purpose of this current review is to summarize advances in our understanding of Notch signaling in skel- * Daniel W. Youngstrom etal physiology that have occurred over the past 2 years. [email protected] A PubMed literature search for (“Notch signaling OR Jagged-1”)AND(“bone OR osteoblast”)between 1 Department of Orthopaedic Surgery, University of Michigan Medical October 2016 and October 2018 returned > 200 results, School, 109 Zina Pitcher Pl, Ann Arbor, MI 48872, USA which were sorted for inclusion by content and 218 Curr Osteoporos Rep (2019) 17:217–225 supplemented with earlier foundational articles. Notch phenotype in the developing limbs [20]. Prx1+ (paired related signaling is highly context-dependent, and experimental homeobox 1) lineage (MPC-targeted) Notch-deficient mice findings across sexes, anatomical sites, and even bone experience an initial pulse of osteoblastogenesis and bone compartments are difficult to broadly generalize. This ar- formation, followed by progressive bone loss due to depletion ticle highlights recent additions to our understanding of of the MPC pool [21]. However, during zebrafish notochord Notch signaling in bone cells, categorized by cell type. epithelial sheath segmentation, Notch signaling encodes the transition of Col9a2+ (collagen type IX alpha 2) cartilaginous Skeletal Morphogenesis to Entpd5a+ (ectonucleoside triphosphate diphosphohydrolase 5a) mineralizing domains in the spine, recruiting early osteo- The translucent zebrafish embryo is a powerful model of early blasts from the paraxial mesenchyme and activating osteoblast skeletal development. In these animals, cranial neural crest transcriptional programs that will form the vertebral bodies cells within the mandibular and hyoid arches develop into [22]. These apparently conflicting roles of Notch signaling the pharyngeal cartilages of the lower face [11]. In this con- in bone formation will remain a consistent and controversial text, Notch signaling partitions the uppermost domain of the theme throughout this review. dorsoventral axis, ultimately specifying the formation of dor- sal arch-derived structures including the palatoquadrate. Jag1b Osteochondral Progenitor Cells (Jagged-1b)-to-Notch2/3 signaling is required for normal de- velopment [12]; Jag1b−/− mutants exhibit dorsal mandibular During development, two discrete phases of Notch signaling and hyoid cartilage defects and die by 7dpf, although other activity regulate the lineage progression of osteoblastic cells: a facial structures develop normally [13]. Jag1b−/− mutants also pattern that is broadly mirrored in adulthood [23]. The first experience reduced dorsal expression of CD248a (endosialin) phase promotes stemness. For example, Notch signaling is and Pou3f3a/b (POU class 3 homeobox 3 a/b), leading to correlated with maintenance of cranial suture patency [24], dorsal arch malformation while ventral/intermediate arch gene and downregulation of Notch signaling is widely believed to expression patterns are unaffected [14•]. One function of be necessary for initial entrance of MPCs into the osteoblast notch signaling in this dorsal arch is to regionally antagonize lineage [25] as well as other lineages [26–28], with significant the Bmp (bone morphogenetic protein)/Edn1 (endothelin 1) input from parallel signaling pathways. This initial wave of signaling of the ventral/intermediate domains, maintaining the Notch is then turned off during differentiation: a mechanistic dorsal arches as undifferentiated progenitor cells and delineat- switch that remains the subject ongoing investigation. ing a gradient of ventral chondrogenesis that patterns the ear- As a niche factor, Notch contributes to MPC resilience. liest facial bone structures [12]. Antagonistic Notch/Edn1 sig- Notch-1 intracellular domain (N1ICD) expression was found naling in zebrafish pharyngeal arch development is conserved to protect bone marrow MPCs from cytotoxicity of cigarette in mice [15]. smoke extract, promoting proliferation and Cxcr4 (C-X-C Constituting a regional positive feedback loop, dorsal motif chemokine receptor 4) expression by activation of the Jag1b/Hey1/Grem2 (gremlin 2) signaling is actively excluded Pi3k (phosphoinositide 3-kinase) cell cycle regulatory path- from the ventral arches [16]. Misexpression of human Jag1 in way [29]. Outside of classical signaling pathways, the re- zebrafish results in dorsalization of the ventral/intermediate sponse of MPCs to osteogenic stimuli is partially regulated arch domains [13], indicating that Notch is not only necessary, by non-coding RNAs. A concentration-dependent, biphasic but sufficient for dorsal arch fate determination [12]. Jag1/2- activation of lncRNA H19 is one mechanism by which posi- to-Notch1/2/3 signaling is also observed in arch and jaw de- tive feedback of Notch and its associated miRNAs down- velopment among Lake Malawi cichlids [17]. More is current- stream of BMP can drive both early proliferation and late ly understood about how Notch signaling restricts early ven- differentiation of osteoblast-lineage cells [30]. tral chondrogenesis than how it drives dorsal domain-specific Parathyroid hormone (PTH) has long been known for its skeletogenesis, though downstream modulation of role in bone homeostasis, and some of this function is due to chondrogenic transcription factors, including Fox proteins, downstream Notch activity. Transient inhibition of Rbpj bind- are one potential mechanism [18]. The increasing use of con- ing induced by PTH in the osteoblast lineage may cause entry ditional transgenesis in zebrafish may help elucidate the role of MPCs into osteoblasts by switching off Notch [31]. of Notch signaling in later perichondral and endochondral Supporting this, conditional deletion of Jag1 in (Prx1-Cre) ossification. MPCs in mice results in premature passage of osteoprogenitor Dysregulation of Notch signaling results in significant cells into anabolic osteoblasts, increasing femoral and tibial limb/fin morphogenic defects [19], due to the pathway’sroles trabecular bone volume fraction and mineral apposition rate, both in regulating progenitor cell populations and
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