Illustration of growth plate stem cells

Unlocking Bone Growth: Stem Cell Discovery in Growth Plates

Rhea Morgan in Health & Wellness October 2026 • 4 min read.

"Scientists identify a unique class of skeletal stem cells in the resting zone of growth plates, offering new insights into bone development and potential therapies."

Bone growth and maintenance rely on skeletal stem cells, which create a variety of cell types, including chondrocytes, osteoblasts, and bone marrow stromal cells. The growth plate, a cartilage-based tissue essential for bone elongation, has been thought to house a unique type of skeletal stem cell. New research sheds light on these elusive cells, detailing their location, function, and regulation within the growth plate.

Parathyroid hormone-related protein (PTHrP) plays a critical role in maintaining the growth plate. It interacts with Indian hedgehog (Ihh), a protein released from the hypertrophic zone, to control chondrocyte production. Until now, the precise identity of skeletal stem cells and their maintenance within the growth plate remained a mystery. This study uncovers a distinct population of PTHrP-positive chondrocytes that exhibit stem cell properties.

Using a mouse model, researchers have pinpointed skeletal stem cells within the resting zone of the postnatal growth plate. These PTHrP-positive chondrocytes express specific markers of skeletal stem and progenitor cells and uniquely possess skeletal stem cell characteristics when cultured. Cell-lineage analysis reveals that these cells continuously form columnar chondrocytes, which then transform into osteoblasts and bone marrow stromal cells beneath the growth plate.

The Resting Zone's Stem Cell Niche: A Dynamic Feedback System

The study's findings indicate that transit-amplifying chondrocytes in the proliferating zone, maintained by signals from undifferentiated (PTHrP) and hypertrophic (Ihh) cells, provide crucial cues for the fate of PTHrP-positive chondrocytes in the resting zone. This intricate feedback loop ensures the proper maintenance and function of these skeletal stem cells.

Key findings include:

Unique Stem Cell Type: Identification of a somatic stem cell that is initially unipotent but gains multipotency after mitosis, showcasing the malleable nature of skeletal cell lineages.
Postnatal Specification: Discovery that dedicated stem cells and their niches are specified postnatally.
Feedback Regulation: Demonstration of a tight feedback regulation system that maintains tissue growth.

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Latest Research

Emerging Growth Plate Stem Cell Findings

Recent research reports that growth plate chondrocytes and hypertrophic chondrocytes can convert into osteoblasts and bone marrow stromal cells, which mainly occupy the metaphysis. Hypertrophic chondrocytes have also been reported to transform into marrow-associated skeletal stem and progenitor cells marked by Pdgfra and Lepr. Other studies identify distinct skeletal stem and progenitor populations in human and mouse skeletal environments, while FoxA2+ long-term stem cells are reported to support growth plate cartilage regeneration after injury.

Counterpoints

Limits and Unresolved Biology

Mesenchymal stem cell impairment has been proposed as a pathological mechanism contributing to osteoporosis and rare inherited skeletal dysplasias. Reviews also emphasize that postnatal skeletal stem and progenitor populations occupy different regions of long bones, including the growth plate. Because recent studies rely on fluorescence-activated cell sorting, lineage tracing, and single-cell sequencing, identifying and interpreting these populations remains technically complex.

Comparison

Diversity Across Niches and Life Stages

Skeletal stem cells underlie skeletal development, homeostasis, regeneration, and aging, but their identities and functions are highly heterogeneous across anatomical sites and life stages. Mouse genetic studies have identified multiple skeletal stem cell populations in distinct niches, including the growth plate, periosteum, and bone marrow. This diversity suggests that growth plate cells should be compared with stem cell populations from other skeletal niches rather than treated as a single uniform population.

Further experiments using Pthrp-creER mice confirmed that PTHrP+ resting chondrocytes give rise to columnar chondrocytes. Lineage tracing with R26RtdTomato mice showed that labeled PTHrP+ cells form short columns initially, then longer columns that contribute to growth plate elongation. Multicolor lineage tracing with R26RConfetti mice demonstrated that individual PTHrP+ resting chondrocytes can generate multiple chondrocyte types clonally.

Implications for Bone Regeneration and Therapy

This research provides a new framework for understanding skeletal stem cell biology and growth plate maintenance. The identification of PTHrP-positive chondrocytes as a unique stem cell population offers potential targets for regenerative therapies.

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Broader Context

The Broader Role of Skeletal Stem Cells

Skeletal stem cells were originally discovered in the bone marrow stroma. They are capable of self-renewal and multilineage differentiation into osteoblasts, chondrocytes, adipocytes, and stromal cells. This broad developmental capacity places skeletal stem cells at the center of research into how bone and related skeletal tissues are maintained and formed.

By understanding the signals that control the fate of these stem cells, researchers may be able to develop strategies to stimulate bone growth, repair cartilage damage, and treat skeletal disorders. Further research will focus on manipulating the PTHrP/Ihh signaling pathway to enhance stem cell activity and promote tissue regeneration.

This study not only advances our fundamental knowledge of skeletal development but also provides a foundation for innovative approaches to skeletal regenerative medicine.

How PTHrP cells compare with other skeletal populations

PTHrP labels a subset of skeletal stem cells in the resting zone, with the marker pattern CD51-positive, CD90-negative, CD105-negative, and CD200-positive. This places them within, rather than outside, the established skeletal-stem-cell marker framework.^[1]

A separate mouse skeletal-stem-cell population is defined as CD45-negative, CD31-negative, Ter119-negative, CD51-positive, CD105-negative, and CD200-positive. Its lack of striking enrichment among Gli1-positive cells was interpreted as evidence that Gli1-negative skeletal stem cells also exist in the growth plate.^[1]

The available flow-cytometry comparisons used eight mice for one Pthrp-mCherry analysis, three control mice, and five mice per group for a Col1a1-GFP analysis, giving the marker results a defined experimental scale rather than a whole-population census.^[2]

What remains unresolved about PTHrP descendants

The evidence leaves open whether the active hypertrophic-chondrocyte-to-metaphyseal-stem-cell transition and the PTHrP-positive lineage represent separate developmental routes.^[3]

Sources

Gli1 labels progenitors during chondrogenesis in postnatal mice (2024)
www.nature.com (www.nature.com, 2018)
Identification of the metaphyseal skeletal stem cell building trabecular bone (2024)

About this Article -

Written with AI assistance from published research, and reviewed by the Mystum team. See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1038/s41586-018-0662-5, Alternate LINK

Title: Resting Zone Of The Growth Plate Houses A Unique Class Of Skeletal Stem Cells

Subject: Multidisciplinary

Journal: Nature

Publisher: Springer Science and Business Media LLC

Authors: Koji Mizuhashi, Wanida Ono, Yuki Matsushita, Naoko Sakagami, Akira Takahashi, Thomas L. Saunders, Takashi Nagasawa, Henry M. Kronenberg, Noriaki Ono

Published: 2018-10-31

Everything You Need To Know

Where are the skeletal stem cells located, and what is their role?

The skeletal stem cells are found in the resting zone of the growth plates. These cells are responsible for bone growth and maintenance. The study indicates that these cells are PTHrP-positive chondrocytes. This is significant because the identification of these cells provides insight into the mechanisms of bone development and potential targets for regenerative therapies.

What is the function of PTHrP-positive chondrocytes in bone development?

The PTHrP-positive chondrocytes are essential in bone growth, they are a type of skeletal stem cells that give rise to various cell types like chondrocytes, osteoblasts, and bone marrow stromal cells. These cells continuously form columnar chondrocytes, which then transform into osteoblasts and bone marrow stromal cells beneath the growth plate. Their function is vital for bone elongation, and any disruption to these cells would impact bone growth.

What is the significance of the growth plate in this research?

The growth plate is a cartilage-based tissue found within bones, and it is essential for bone elongation. The study reveals that the growth plate houses a unique type of skeletal stem cell, specifically PTHrP-positive chondrocytes, which are responsible for bone growth. Understanding these cells' role within the growth plate is crucial for developing regenerative medicine and therapies related to bone and cartilage.

What is the role of PTHrP in bone growth?

PTHrP, or Parathyroid hormone-related protein, plays a crucial role in maintaining the growth plate by interacting with Indian hedgehog (Ihh). Ihh is a protein released from the hypertrophic zone, which helps control chondrocyte production. The study found that PTHrP-positive chondrocytes exhibit stem cell properties. This interaction and the identification of these cells are critical for the proper maintenance and function of skeletal stem cells.

How does the growth plate maintain its function and structure?

This research uncovers a dynamic feedback system within the growth plate. Transit-amplifying chondrocytes in the proliferating zone provide cues for the fate of PTHrP-positive chondrocytes in the resting zone, which ensures the proper maintenance and function of these skeletal stem cells. This feedback loop is crucial for maintaining bone growth and represents a complex interaction between different zones and cell types within the growth plate.