The Role of GH/IGF Axis in Dento-Alveolar Complex from Development to Aging and Therapeutics: A Narrative Review

Abstract

The GH/IGF axis is a major regulator of bone formation and resorption and is essential to the achievement of normal skeleton growth and homeostasis. Beyond its key role in bone physiology, the GH/IGF axis has also major pleiotropic endocrine and autocrine/paracrine effects on mineralized tissues throughout life. This article aims to review the literature on GH, IGFs, IGF binding proteins, and their respective receptors in dental tissues, both epithelium (enamel) and mesenchyme (dentin, pulp, and tooth-supporting periodontium). The present review re-examines and refines the expression of the elements of the GH/IGF axis in oral tissues and their in vivo and in vitro mechanisms of action in different mineralizing cell types of the dento-alveolar complex including ameloblasts, odontoblasts, pulp cells, cementoblasts, periodontal ligament cells, and jaw osteoblasts focusing on cell-specific activities. Together, these data emphasize the determinant role of the GH/IGF axis in physiological and pathological development, morphometry, and aging of the teeth, the periodontium, and oral bones in humans, rodents, and other vertebrates. These advancements in oral biology have elicited an enormous interest among investigators to translate the fundamental discoveries on the GH/IGF axis into innovative strategies for targeted oral tissue therapies with local treatments, associated or not with materials, for orthodontics and the repair and regeneration of the dento-alveolar complex and oral bones.

Keywords: GH; IGF; IGFBP; age-related pathologies; alveolar bone; animal models; bone repair; dental ligament; dentin; dentin repair; enamel; mandible; oral tissue engineering; orthodontic treatment; osseointegration; periodontal regeneration; tooth.

Figure 1

The dento-alveolar development. (A) Epithelial cells (in brown) interact with ecto-mesenchymal cells (in green) forming the bud, cap, and bell. The final erupted tooth is formed with the crown and the root anchored in the alveolar bone. The most external layer of the crown is the enamel (in white), which is synthesized by ameloblasts. The dentin (in yellow) is synthesized by the odontoblasts and the pulp contains DPCs, DPSCs, nerves, and vessels; (B) The rodent continually growing incisor summarizes the whole process of odontogenesis. First, precursor cells (expressing high levels of GHR and IGF-1R) are proliferating in the cervical loop, then cells differentiate either into ameloblasts that secrete enamel matrix proteins (in white), or into odontoblasts that synthesize the dentin (in yellow). At the end of amelogenesis, ameloblasts are lost, leading to an acellular and irreparable enamel matrix; (C) In human and rodent molars, the precursor cells are localized near the forming root involving odontoblasts, HERS, osteoblasts, and osteoclasts of the alveolar bone. During enamel synthesis, ameloblasts differentiate and change their shape and function. During dentin synthesis, odontoblast body cells move away from the DEJ, thus reducing the volume of the pulp chamber. The space between the dental root and the alveolar bone is formed by the fibroblasts, PDLCs and the cementoblasts lining the tooth, forming ligament fibers that attach the tooth to the bone. SCAPs are associated to the apex of a developing root, they may be recruited in case of necrotic pulp in order to complete root development and apexogenesis. DEJ: dentin- enamel junction, DPCs: dental pulp cells, DPSCs: dental pulp stem cells, GHR: growth hormone receptor, HERS: Hertwig epithelial root sheath, IGF-1R: insulin-like growth factor 1 (IGF1) receptor, PDLCs: periodontal ligament cells, SCAPs: Stem cells from the apical papilla.

Figure 2

Expression of IGF components in the dento-alveolar complex. (A) Schematic representation of a sagittal section of a rodent hemi-mandible with the bone in blue, the teeth (3 molars and the growing incisor in white), the dental epithelium in red, the dental mesenchyme in green, and the dentin in yellow. There are many immature proliferating cells in the selected area especially in the cervical loop with cells expressing high levels of GHR and IGF-1R. Osteoblasts, odontoblasts, cementoblasts, periodontal ligament cells are responsive to GH, which increases the level of differentiation markers such as BMP2, BMP4, ALP, col1α1, and IGF1. IGFBP5 promotes IGF1 activity, which up-regulates RUNX2 expression. RUNX2 decreases IGFBP2 expression, thus promoting IGF1 action also; (B) Schematic magnification of odontogenesis. DPCs (in green) express GHR, IGF-1R, IGF1, and mostly IGFBP4 and IGFBP5 in addition to IGFBP3 and IGFBP2. In the CL, immature proliferating cells express high levels of GHR and IGF-1R. During odontoblast differentiation (yellow cells), GHR and IGF-1R, as well as IGF2 and IGF1, are decreasingly expressed during the whole differentiation process with first IGFBP2 and IGFBP3, then mainly IGFBP5. During amelogenesis, pre-ameloblasts express high levels of GHR and IGF-1R, whose expression decreases during the secretion and the transition stages. During the maturation, corresponding to enamel terminal mineralization, IGF-1R is highly expressed in RA, as well as IGFBP2 and IGFBP3, and to as lesser extend IGFBP5 and IGFBP4. IGFBP6, which inhibits IGF2 action, seems expressed in HERS only (not shown here). ALP: alkaline phosphatase, BMP2, 4: bone morphogenetic protein 2, 4, CL: cervical loop, Col1α1: Collagen 1α1, DPCs: dental pulp cells, GHR: growth hormone (GH) receptor, HERS: Hertwig epithelial root sheath, IGFBP2, 3, 4, 5: insulin-like growth factor-binding protein 2, 3, 4, 5, IGF-1R: insulin-like growth factor 1 (IGF1) receptor RA: ruffle-ended ameloblasts, RUNX2: Runt-related transcription factor 2.

Figure 3

Pathologies of the dento-alveolar complex and therapeutic solutions. (A) Dentin and dental pulp diseases with pulp exposures (due to dental decay, fractures, or iatrogenic injuries) activate tertiary dentin synthesis and could be treated with material for pulp capping associated or not with bioactive components of the GH/IGF axis; (B) Periodontal diseases (due to infections) are generally associated with gingiva and bone loss need to be filled with biomaterials possibly associated with bioactive components of the GH/IGF axis; (C) Implant osseointegration requires alveolar bone regeneration and could be improved with bioactive components of GH/IGF axis. GH: growth hormone, IGF1: insulin-like growth factor 1, w/wo: with/without.

Figure 4

Surgical procedures with rhGH treatments for mandibular size corrections in case of mandibular growth defects. (A) Initial position of the ingrowing mandible; (B) Osteotomy and placement of distractors; (C) Activation of distractors; (D) Healing and osteogenesis period; (E) Maturation of newly formed bone; (F) Final position where normal bone modeling and remodeling are taking place.