Shh Signaling from the Nucleus Pulposus Is Required for the Postnatal Growth and Differentiation of the Mouse Intervertebral Disc

Division of Orthopaedic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
PLoS ONE (Impact Factor: 3.23). 04/2012; 7(4):e35944. DOI: 10.1371/journal.pone.0035944
Source: PubMed


Intervertebral discs (IVD) are essential components of the vertebral column. They maintain separation, and provide shock absorbing buffers, between adjacent vertebrae, while also allowing movements between them. Each IVD consists of a central semi-liquid nucleus pulposus (NP) surrounded by a multi-layered fibrocartilagenous annulus fibrosus (AF). Although the IVDs grow and differentiate after birth along with the vertebral column, little is known about the mechanism of this. Understanding the signals that control normal IVD growth and differentiation would also provide potential therapies for degenerative disc disease, which is the major cause of lower back pain and affects a large proportion of the population. In this work, we show that during postnatal growth of the mouse, Sonic hedgehog (Shh) signaling from the NP cells controls many aspects of growth and differentiation of both the NP cells themselves and of the surrounding AF, and that it acts, at least partly, by regulating other signaling pathways in the NP and AF. Recent studies have shown that the NP cells arise from the embryonic notochord, which acts as a major signaling center in the embryo. This work shows that this notochord-derived tissue continues to carry out a major signaling function in the postnatal body and that the IVDs are signaling centers, in addition to their already known functions in the mechanics of vertebral column function.

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    • "Targeted ablation of β-catenin in type II collagen expressing cells lead to CEP calcification; conversely, ectopic activation of β-catenin in the AF and vertebral growth plate resulted in severe deterioration of both structures[163]. This may be a direct effect of Wnt/β-catenin activation or an indirect effect mediated by altered SHH signaling, given the feedback between these two pathways in the NP[164,165]. Interestingly, in the adult NP expression of both SHH and Wnt/β-catenin are downregulated, as are Wnt targets in the whole IVD[164]. "

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    • "Moreover, it was demonstrated that the heparan-sulphate side chains of SDC4 were involved in controlling the expression of another critical factor, Sox9 that is involved in the regulation of aggrecan and collagen II expression. Numerous studies have also highlighted roles of multiple morphogenic factors during the development of the IVD, including FGF-2, BMP-2, sonic hedgehog (Shh), Ihh amongst others[55,56]. It is known that these molecules interact with heparan-sulphate within their environment to mediate binding to their receptors. "
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    ABSTRACT: The ECM of the intervertebral disc and articular cartilage contain a highly organised network of collagens and proteoglycans which resist compressive forces applied to these tissues. A pathological hallmark of the intervertebral disc is the imbalance between production of anabolic and catabolic factors by the resident cells. This process is thought to be mediated by pro-inflammatory cytokines, predominantly TNF-α and IL-1β, which upregulate expression of matrix degrading enzymes such as MMPs and ADAMTSs. This imbalance ultimately results in tissue degeneration causing failure of the biomechanical function of the tissues. A similar cascade of events is thought to occur in articular cartilage during development of osteoarthritis. Within these skeletal tissues a small, cell surface heparan sulphate proteoglycan; syndecan-4 (SDC4) has been implicated in maintaining physiological functions. However in the degenerating niche of the intervertebral disc and cartilage, dysregulated activities of this molecule may exacerbate pathological changes. Studies in recent years have elucidated a role for SDC4 in mediating matrix degradation in both intervertebral discs and cartilage by controlling ADAMTS-5 function and MMP3 expression. Discourse presented in this review highlights the potential of SDC4 as possible therapeutic target in slowing the progression of ECM degradation in both degenerative disc disease and osteoarthritis.
    Full-text · Article · Jan 2016 · Matrix biology: journal of the International Society for Matrix Biology
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    • "We have demonstrated that Shh signaling is both necessary and sufficient for cell proliferation in the NP during postnatal growth [8]. Therefore we assayed for cell proliferation following activation or blockade of canonical Wnt signaling. "
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    ABSTRACT: Intervertebral discs (IVDs) are strong fibrocartilaginous joints that connect adjacent vertebrae of the spine. As discs age they become prone to failure, with neurological consequences that are often severe. Surgical repair of discs treats the result of the disease, which affects as many as one in seven people, rather than its cause. An ideal solution would be to repair degenerating discs using the mechanisms of their normal differentiation. However, these mechanisms are poorly understood. Using the mouse as a model, we previously showed that Shh signaling produced by nucleus pulposus cells activates the expression of differentiation markers, and cell proliferation, in the postnatal IVD. In the present study, we show that canonical Wnt signaling is required for the expression of Shh signaling targets in the IVD. We also show that Shh and canonical Wnt signaling pathways are down-regulated in adult IVDs. Furthermore, this down-regulation is reversible, since re-activation of the Wnt or Shh pathways in older discs can re-activate molecular markers of the IVD that are lost with age. These data suggest that biological treatments targeting Wnt and Shh signaling pathways may be feasible as a therapeutic for degenerative disc disease.
    Full-text · Article · Jun 2014 · PLoS ONE
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