The Roles of Indian Hedgehog Signaling in TMJ Formation.

Till E. Bechtold,Naito Kurio,Eiki Koyama,Cheri Saunders,Paul C. Billings,Hyun-Duck Nah

doi:10.3390/ijms20246300

Abstract

The temporomandibular joint (TMJ) is an intricate structure composed of the mandibular condyle, articular disc, and glenoid fossa in the temporal bone. Apical condylar cartilage is classified as a secondary cartilage, is fibrocartilaginous in nature, and is structurally distinct from growth plate and articular cartilage in long bones. Condylar cartilage is organized in distinct cellular layers that include a superficial layer that produces lubricants, a polymorphic/progenitor layer that contains stem/progenitor cells, and underlying layers of flattened and hypertrophic chondrocytes. Uniquely, progenitor cells reside near the articular surface, proliferate, undergo chondrogenesis, and mature into hypertrophic chondrocytes. During the past decades, there has been a growing interest in the molecular mechanisms by which the TMJ develops and acquires its unique structural and functional features. Indian hedgehog (Ihh), which regulates skeletal development including synovial joint formation, also plays pivotal roles in TMJ development and postnatal maintenance. This review provides a description of the many important recent advances in Hedgehog (Hh) signaling in TMJ biology. These include studies that used conventional approaches and those that analyzed the phenotype of tissue-specific mouse mutants lacking Ihh or associated molecules. The recent advances in understanding the molecular mechanism regulating TMJ development are impressive and these findings will have major implications for future translational medicine tools to repair and regenerate TMJ congenital anomalies and acquired diseases, such as degenerative damage in TMJ osteoarthritic conditions.

Highlights

The temporomandibular joint (TMJ), like joints in the shoulder, hip, and knee, is a highly specialized synovial joint and plays a pivotal role in the functioning of the mammalian jaw [1,2,3,4,5]
Given the fact that the number of proliferating chondroprogenitor cells was drastically decreased and chondrocytes underwent accelerated hypertrophy in Indian hedgehog (Ihh)−/− condyles, it is likely that parathyroid hormone-related protein (PTHrP) induced by Ihh signaling may (1) regulate the proliferation of chondro-progenitor cells and (2) maintain newly differentiated chondrocytes in a less differentiated stage
Expression of Hh target genes and β-galactosidase activity in hedgehog reporter mice indicated that an Ihh signaling gradient across the condylar cartilage may contribute to cell progenitor layer; fc, flattened chondrocyte layer; ph/hc, perhypertrophic/hypertrophic chondrocyte Int

Summary

Introduction

The temporomandibular joint (TMJ), like joints in the shoulder, hip, and knee, is a highly specialized synovial joint and plays a pivotal role in the functioning of the mammalian jaw [1,2,3,4,5]. As taking place in developing condylar cartilage, chondrocytes differentiate amongst type I collagen (Col I)-expressing mesenchymal cells in a presumptive articulating layer covering the temporal bone where the condyle articulates, exhibiting features of secondary cartilage-like condylar cartilage [24,25]. Human patients carrying mutations in Gli exhibit a range of facial defects, including mandibular hypoplasia [4,61] These observations provide strong evidence that Ihh signaling dictates the cellular organization of the condyle and regulates disc formation and subsequent joint cavitation. 50%) and chondrocytes underwent accelerated hypertrophy in Ihh−/− condyles, it is likely that PTHrP induced by Ihh signaling may (1) regulate the proliferation of chondro-progenitor cells and (2) maintain newly differentiated chondrocytes in a less differentiated stage. Figure modified from Ochiai et al [69]

Effect of Conditional Ihh Signaling Ablation in Postnatal Stages

Findings

Hh Signaling in Degenerative TMJs