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Development of Migrating Tendon-Bone Attachments Involves © 2018. Published by The Company of Biologists Ltd | Development (2018) 145, dev165381. doi:10.1242/dev.165381 RESEARCH ARTICLE Development of migrating tendon-bone attachments involves replacement of progenitor populations Neta Felsenthal1, Sarah Rubin1, Tomer Stern1, Sharon Krief1, Deepanwita Pal2, Brian A. Pryce2, Ronen Schweitzer2 and Elazar Zelzer1,* ABSTRACT tissue (Doschak and Zernicke, 2005; Shaw and Benjamin, 2007; Tendon-bone attachment sites, called entheses, are essential for Wang et al., 2013), has been shown to be regulated by parathyroid musculoskeletal function. They are formed embryonically by Sox9+ hormone-like hormone (PTHLH, also known as PTHrP) (Wang progenitors and continue to develop postnatally, utilizing Gli1 lineage et al., 2013). Fibrocartilage entheses typically form at attachment cells. Despite their importance, we lack information on the transition sites of tendons to the epiphysis or to bone eminences. Relative from embryonic to mature enthesis and on the relation between Sox9+ to fibrous entheses, fibrocartilage entheses are structurally more progenitors and the Gli1 lineage. Here, by performing a series of complex, displaying a cellular gradient that is typically divided lineage tracing experiments in mice, we identify the onset of into four zones, namely tendon, fibrocartilage, mineralized Gli1 lineage contribution to different entheses. We show that Gli1 fibrocartilage and bone. The graded tissue, which develops expression is regulated embryonically by SHH signaling, whereas postnatally, dissipates the stress that forms at the attachment site, postnatally it is maintained by IHH signaling. During bone elongation, thereby providing the enthesis with the mechanical strength some entheses migrate along the bone shaft, whereas others necessary to withstand compression (Benjamin et al., 2006). remain stationary. Interestingly, in stationary entheses Sox9+ cells Enthesis development is initiated by the specification of a differentiate into the Gli1 lineage, but in migrating entheses this specialized pool of progenitor cells that express both SRY-box 9 Sox9 lineage is replaced by Gli1 lineage. These Gli1+ progenitors are ( ), a key regulator of chondrogenesis, and the tendon marker Scx defined embryonically to occupy the different domains of the mature scleraxis ( ) (Akiyama et al., 2005; Blitz et al., 2013; Schweitzer enthesis. Overall, these findings demonstrate a developmental et al., 2001; Sugimoto et al., 2013). Cell lineage studies have shown Sox9 strategy whereby one progenitor population establishes a simple that -expressing progenitor cells contribute to the formation of embryonic tissue, whereas another population contributes to its the enthesis in neonatal mice (Akiyama et al., 2005; Soeda et al., maturation. Moreover, they suggest that different cell populations may 2010). Another marker for enthesis cells is GLI-Kruppel family Gli1 be considered for cell-based therapy of enthesis injuries. member GLI1 ( ; Liu et al. 2012), a component of the hedgehog (HH) signaling pathway. Lineage studies revealed that Gli1- KEY WORDS: Musculoskeletal development, Enthesis, Sox9, Gli1, expressing cells act as progenitors that contribute to the formation Progenitor cell, Hedgehog signaling, R26R-Confetti, Mouse of some adult entheses (Dyment et al., 2015; Schwartz et al., 2015). However, the relationship between progenitors of the embryonic INTRODUCTION enthesis and Gli1 lineage cells, which contribute to the mature The proper assembly of the musculoskeletal system is essential for enthesis, has not been determined. the function, form and stability of the organism. During The relative position of an enthesis along the bone directly affects embryogenesis, an attachment between tendon and bone, known its mechanical function and, subsequently, the animal’s mobility as an enthesis, is formed. Thereafter, and into the postnatal period, (Polly, 2007; Salton and Sargis, 2009). Recently, it was shown that the rudimentary enthesis further develops into a more complex all entheses maintain their relative position during bone elongation tissue. Although some knowledge on enthesis formation and (Stern et al., 2015). Unlike entheses located at the bone ends, from maturation exists, far less is known about the processes that which the bone elongates, entheses that are located between transform the simple embryonic enthesis into the structure of the the epiphyseal plates must maintain their positions during growth. mature enthesis. This was shown to occur through either regulation of the relative Traditionally, entheses are divided into either fibrous or growth rates at the two epiphyseal plates, or active migration by fibrocartilaginous, according to their cellular composition. Fibrous continuous reconstruction, a process known as bone modeling or entheses form at the attachment site of a tendon that is inserted drift (Benjamin and McGonagle, 2009; Dörfl, 1980a,b). The latter directly into the bone shaft, forming a structure that resembles a root (referred to hereafter as migrating entheses) encounters a unique system. This structure, which is composed of a dense connective developmental challenge. Unlike most organs and tissues, entheses must develop into a complex graded tissue while constantly drifting. This raises the issue of whether the descendants of the embryonic 1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot enthesis progenitors continue to serve as the building blocks during 76100, Israel. 2Research Division, Shriners Hospital for Children, Portland, OR 97201, USA. maturation of migrating entheses. In this work, we identify the embryonic stage at which Gli1 *Author for correspondence ([email protected]) lineage is initiated and demonstrate its contribution to the postnatal Gli1 N.F., 0000-0003-4927-7679; T.S., 0000-0003-4279-3558; R.S., 0000-0002- enthesis. We show that embryonic expression is initially under 7425-5028; E.Z., 0000-0002-1584-6602 the regulation of sonic hedgehog (SHH). Later during postnatal development, Gli1 expression is maintained by Indian hedgehog Received 7 March 2018; Accepted 16 November 2018 (IHH). Moreover, we show that Sox9 lineage does not contribute to DEVELOPMENT 1 RESEARCH ARTICLE Development (2018) 145, dev165381. doi:10.1242/dev.165381 postnatal migrating entheses. Instead, Gli1 lineage cells replace the Analysis of enthesis positions during development revealed that Sox9 lineage cells and populate the enthesis. Finally, we show that both DT (0.778±0.026 mm, data are mean±s.d.) and TM (1.624± embryonic Gli1 lineage cells are pre-determined to contribute to the 0.171 mm) entheses drifted considerably along the bone shaft during different layers of the fibrocartilaginous enthesis. bone elongation (Fig. 1A). Histological sections through wild-type (WT) mouse humeri showed that both embryonic entheses displayed a RESULTS simple structure of layered cells (Fig. 1B,Ca,Da). However, the overall Some entheses undergo cellular and morphological changes shape of the enthesis changed dramatically throughout development, during migration as it protruded outwards from the bone shaft and the different enthesis The development of the rudimentary embryonic attachment site into domains became more noticeable (Fig. 1Ca′-Ca‴,Da′-Da‴). Tissue the complex structure of a mature enthesis has received little attention complexity also increased, as a larger variety of cells, such as (Galatz et al., 2007). As mentioned, in addition to substantial cellular fibrocartilage cells and osteoblasts (Benjamin and McGonagle, 2009), and morphological changes, some entheses also migrate considerable were identified along with an increase in extracellular matrix distances along the bone during bone growth (Benjamin and (Fig. 1Cd,Cd′,Ch,Ch′,Dd,Dd′,Dh,Dh′). The increased complexity McGonagle, 2009; Dörfl, 1980a,b; Stern et al., 2015). Therefore, was also demonstrated by a change in the expression patterns of to study the transition that migrating entheses undergo during structural genes, such as bone sialoprotein (Bsp;alsoknownas maturation, we documented morphological and molecular changes, integrin binding sialoprotein, Ibsp), collagen type 2 alpha 1 (Col2a1), as well as drifting activity, in entheses from embryonic day (E) 14.5 collagen type 12 alpha 1 (Col12a1) and tenascin C (Tnc), and to postnatal day (P) 14. We focused on two migrating entheses, regulatory genes such as Gli1. Furthermore, expression domains namely the deltoid enthesis (DT), a fibrocartilaginous enthesis that correlating to various structural domains emerged, namely Col12a1, forms between the deltoid tendon and the deltoid tuberosity, and the Tnc, Gli1 and Col1a1 in tendon and fibrocartilage (Fig. 1Cc,Cf-Ch, teres major enthesis (TM), a fibrous enthesis that forms between the Dc,Df-Dh), and Col1a1, Gli1 and Bsp in mineralized fibrocartilage teres major tendon and the humeral shaft. and bone (Fig. 1Cc,Ce,Ch,Dc,De,Dh). Fig. 1. Some entheses undergo cellular and morphological changes while migrating. (A) Graph showing the physical position of the DT and TM entheses along the bone throughout development (E16.5-P14), defined as the distance of the element (mm) from a predefined longitudinal origin roughly at the center of the shaft. Positive and negative values correspond to elements that are proximal and distal to the point of origin, respectively. As indicated by the steep slope of the curves, both DT and TM migrate considerably throughout development. (B) Schematics of the embryonic DT and TM entheses.
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