Recent Insights into Long Bone Development: Central Role of Hedgehog Signaling Pathway in Regulating Growth Plate

Abstract

The longitudinal growth of long bone, regulated by an epiphyseal cartilaginous component known as the “growth plate”, is generated by epiphyseal chondrocytes. The growth plate provides a continuous supply of chondrocytes for endochondral ossification, a sequential bone replacement of cartilaginous tissue, and any failure in this process causes a wide range of skeletal disorders. Therefore, the cellular and molecular characteristics of the growth plate are of interest to many researchers. Hedgehog (Hh), well known as a mitogen and morphogen during development, is one of the best known regulatory signals in the developmental regulation of the growth plate. Numerous animal studies have revealed that signaling through the Hh pathway plays multiple roles in regulating the proliferation, differentiation, and maintenance of growth plate chondrocytes throughout the skeletal growth period. Furthermore, over the past few years, a growing body of evidence has emerged demonstrating that a limited number of growth plate chondrocytes transdifferentiate directly into the full osteogenic and multiple mesenchymal lineages during postnatal bone development and reside in the bone marrow until late adulthood. Current studies with the genetic fate mapping approach have shown that the commitment of growth plate chondrocytes into the skeletal lineage occurs under the influence of epiphyseal chondrocyte-derived Hh signals during endochondral bone formation. Here, we discuss the valuable observations on the role of the Hh signaling pathway in the growth plate based on mouse genetic studies, with some emphasis on recent advances.

Interaktion zwischen Muskel und Knochen – ein Wechselspiel zwischen Physik und Biologie

“…Die Core-Signaltransduktionswege für die Knochenneubildung sind osteogene wnt-Signalkaskaden, die Signalkaskaden über den Parathormonrezeptor (PTH1R) und seine Liganden PTH und PTHrP und die Bone Morphogenetic Proteins (BMP), die über Rezeptoren der TGFβ-Familie wirken [42,43]. In den letzten Jahren haben eine Reihe weiterer Signalwege in der osteogenen Differenzierung während der Entwicklung und im Erwachsenenalter Bedeutung erlangt, vor allem die Signalwege, die über HIPPO, YAP/TAZ, NOTCH und Hedgehog vermittelt werden [44][45][46]. Besonders die osteogenen Signalwege über wnt-Kaskaden und die PTH1R-Signale sprechen auf mechanische Reize an.…”

Hedgehog Inhibitors Suppress Osteoclastogenesis in In Vitro Cultures, and Deletion of Smo in Macrophage/Osteoclast Lineage Prevents Age-Related Bone Loss

“…Hedgehog (Hh) signaling, well-known as a mitogen and morphogen during animal development, also regulates adult tissue homeostasis and tumorigenesis [1][2][3][4]. Hh ligands in mammals are three proteins, Indian hedgehog (Ihh), Sonic hedgehog, and Desert hedgehog; although they are expressed in different cells and tissues, their functions are not considered different [5,6].…”

“…The Hh-signaling pathway contributes to skeletal development, bone homeostasis, and the progression of tumor bone metastasis. During endochondral ossification, Ihh produced by hypertrophic chondrocytes stimulates osteoblastic bone formation by promoting the expression of Runx2, which is known as a master transcription factor for osteoblast differentiation [2,17,18]. The study of Rodda and McMahon revealed that Hh signaling is not required in the early differentiation phase of an osteoblast for further osteoblast maturation [19].…”

Quick and Abnormal Ossification Results in No Growth Plate Formation and Skeletal Dysplasia in Postnatal Mice Induced by Conditional Knockout of Indian Hedgehog

“…In mammals, the growth plate is composed of three types of highly organized and specialized cartilage: resting zone chondrocytes, proliferative zone chondrocytes, and hypertrophic zone chondrocytes. The growth plate provides a continuous supply of chondrocytes for endochondral ossi cation, whereby limb mesenchyme cells form an intermediate cartilage scaffold that develops into growth plate and is then replaced by bone, and any failure in this process causes a wide range of skeletal disorders [2]. The formation and function of the growth plate is a particularly important topic of research in the prevention of skeletal abnormalities.…”