Decoding growth hormone actions on human growth plate stem cells

Abstract

The epiphyseal growth plate is the key target of growth hormone (GH) therapy. Although growth plate stem cells are well defined in mice, their presence in humans was unclear. Using rare surgical specimens, the study by Chu et al. reveals conserved, GH-responsive stem cells in the human pubertal growth plate.

Growth hormone (GH) is a cornerstone therapy for pediatric growth disorders. GH stimulates longitudinal bone growth through both direct activation of the GH receptor (GHR) and indirect actions mediated by liver-produced insulin-like growth factor 1 (IGF-1). The epiphyseal growth plate, located at the ends of long bones, is responsible for bone elongation during a growth spurt and serves as the key target of GH therapy. However, clinical responses to GH vary widely among patients, and its efficacy often diminishes with prolonged treatment. Identifying the precise cellular targets of GH within the growth plate is therefore essential for improving therapeutic strategies and enhancing growth outcomes.

Much of our current understanding of postnatal growth plate biology derives from transgenic mouse models, including in vivo lineage-tracing and functional genetic studies. These investigations have identified multiple populations of growth plate stem cells (GPSCs) residing in the resting zone, such as parathyroid hormone-related protein (PTHrP)⁺ [1], FoxA2⁺ [2], and ApoE⁺ [3] cells. These stem cells are maintained within a specialized epiphyseal niche carved out during secondary ossification [4], which provides a tightly regulated microenvironment [5]. Fundamental stem cell behaviors of GPSCs, including self-renewal and differentiation, are governed by signaling pathways such as Hedgehog [6], mTORC1 [4], and GHR [7] signaling. Pharmacological activation of these pathways, including treatment with GH or Hedgehog agonists, has been shown to enhance growth plate activity and longitudinal bone growth in rodents [7,8]. Collectively, these studies strongly support a central role for GPSCs in promoting longitudinal bone growth, at least in rodent models.

Despite these advances, a critical question remains: do comparable GPSC populations exist in human growth plates, and if so, do they respond directly to GH in a similar manner? This question is of high translational importance, as human and mouse growth plates are structurally similar but behave substantially different – most notably, the human growth plate undergoes closure during late adolescence, whereas the mouse growth plate remains open. Addressing this gap has been challenging due to limited access to human growth plate tissue.

In this context, Chu et al. [9] leveraged a rare clinical opportunity by analyzing growth plate samples obtained during epiphysiodesis, a growth-restricting procedure performed in patients with idiopathic tall stature. This procedure is performed only in selected institutions for a few cases each year. It is noteworthy that the authors went far beyond what is customarily done with live patient samples – not only did they profile the cellular composition of the human growth plate by single-cell RNA sequencing (scRNA-seq), but they also performed explant “slice” culture to directly assess its responsiveness to GH. The combined approach represents a significant technical and conceptual advance, enabling functional interrogation of human growth plate biology.

The findings are both reassuring and compelling. The authors demonstrate that the cellular architecture of human growth plates is highly conserved relative to that of mice, including the presence of two distinct populations of PTHrP-negative and PTHrP-positive GPSCs (Figure 1). This conserved dual stem cell organization – akin to that recently reported in the cranial suture [10] – suggests that the fundamental principles of growth plate biology are shared across species. Notably, GHR expression was enriched in GPSCs, whereas IGF1R expression predominated in hypertrophic chondrocytes, providing a mechanistic explanation for GH’s preferential direct action on stem cell populations. In explant cultures, GH directly activated canonical JAK/STAT signaling and noncanonical pathways, including TGF-β and ERK1/2 signaling, while suppressing AKT signaling. Together, these results provide strong evidence that GH directly targets stem cells in the human pubertal growth plates and modulates their biological behavior.

Figure 1. Direct actions of growth hormone on human growth plate stem cells.

Growth hormone (GH) directly targets human growth plate stem cells, activating canonical JAK/STAT signaling as well as noncanonical ERK1/2 and TGF-β pathways, while suppressing AKT signaling. These direct actions complement the indirect actions of GH mediated by liver-produced IGF-1, which primarily acts on hypertrophic chondrocytes. Notably, the human growth plate retains a conserved dual stem cell organization consisting of PTHrP-negative and PTHrP-positive stem cells, each exhibiting distinct responses to GH and other systemic signals. This figure was created using BioRender (www.biorender.com).

This work represents a major milestone in the field, validating the relevance of the preclinical findings in mouse models and establishing GPSCs as key mediators of GH-driven bone growth in humans. Conceptually, it positions postnatal growth plate stem cells as central regulators of longitudinal bone growth and as the primary target of endocrine signaling.

At the same time, the study raises important questions. First, because of the inherent limitations of explant culture systems, the authors did not examine the mechanisms underlying the waning efficacy of GH therapy over time. Addressing this clinically important issue may require the development of more translationally relevant in vivo models. Second, while the conservation of GPSC populations between species is encouraging, it does not explain the fundamental difference in growth plate closure between humans and mice. The authors note that the human pubertal growth plate retains a relatively large resting zone and propose that growth cessation may involve remodeling of the stem cell niche. This raises the intriguing possibility that stem cell exhaustion is driven more by extrinsic microenvironmental cues than by intrinsic genetic programs. Indeed, continued growth into adulthood in patients with aromatase or estrogen receptor deficiency underscores the importance of extrinsic hormonal regulation in growth plate closure. If so, could niche modulation extend the functional lifespan of the growth plate in growth-deficient patients?

Addressing these questions will be critical for advancing the field. Beyond refining our understanding of GH biology, such efforts may uncover new therapeutic strategies that target growth plate stem cells or their niche. With the establishment of a robust conceptual and experimental framework, growth plate stem cell biology is now poised to drive transformative advances in the treatment of growth disorders.