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PTHrP and Indian hedgehog control differentiation of growth plate chondrocytes at multiple steps
Tatsuya Kobayashi1, Ung-Il Chung, Ernestina Schipani
1Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
Insights
Indian hedgehog (Ihh) promotes early chondrocyte differentiation independently of parathyroid hormone-related peptide (PTHrP). This study clarifies Ihh and PTHrP roles in regulating chondrocyte development through novel mouse models.
Area of Science:
- Skeletal biology
- Endocrinology
- Developmental biology
Background:
- Chondrocyte differentiation in murine growth plates involves sequential steps from periarticular to columnar and then hypertrophic cells.
- Indian hedgehog (Ihh) and parathyroid hormone-related peptide (PTHrP) are key regulators, with Ihh stimulating PTHrP, which inhibits terminal differentiation via the PTH/PTHrP receptor (PPR).
- The precise roles of Ihh and PTHrP in earlier chondrocyte differentiation stages remain incompletely understood.
Purpose of the Study:
- To elucidate the roles of Ihh and PTHrP in regulating early chondrocyte differentiation using novel mouse models with altered PPR signaling.
- To investigate the interplay between Ihh and PTHrP in controlling chondrocyte maturation.
Main Methods:
- Generation and analysis of mouse models with chondrocyte-specific PPR ablation, reduced PPR expression, and partial PPR disruption in columnar chondrocytes.
- Assessment of chondrocyte differentiation progression, including periarticular to columnar transition.
- Evaluation of Ihh signaling pathway activity in periarticular chondrocytes.
Main Results:
- Mice with global or partial PPR deficiency exhibited accelerated chondrocyte differentiation, including the periarticular to columnar stage.
- Upregulation of Ihh signaling was observed in periarticular regions of PPR-altered mice.
- These findings suggest Ihh positively regulates periarticular chondrocyte differentiation independently of PTHrP.
Conclusions:
- Ihh acts as a positive regulator of early chondrocyte differentiation, specifically the periarticular to columnar transition.
- PTHrP and Ihh mutually regulate each other's activities to control chondrocyte differentiation at multiple developmental stages.
- The study provides new insights into the complex molecular mechanisms governing skeletal development.
Abstract:
In developing murine growth plates, chondrocytes near the articular surface (periarticular chondrocytes) proliferate, differentiate into flat column-forming proliferating cells (columnar chondrocytes), stop dividing and finally differentiate into hypertrophic cells. Indian hedgehog (Ihh), which is predominantly expressed in prehypertrophic cells, stimulates expression of parathyroid hormone (PTH)-related peptide (PTHrP) which negatively regulates terminal chondrocyte differentiation through the PTH/PTHrP receptor (PPR). However, the roles of PTHrP and Ihh in regulating earlier steps in chondrocyte differentiation are unclear. We present novel mouse models with PPR abnormalities that help clarify these roles. In mice with chondrocyte-specific PPR ablation and mice with reduced PPR expression, chondrocyte differentiation was accelerated not only at the terminal step but also at an earlier step: periarticular to columnar differentiation. In these models, upregulation of Ihh action in the periarticular region was also observed. In the third model in which the PPR was disrupted in about 30% of columnar chondrocytes, Ihh action in the periarticular chondrocytes was upregulated because of ectopically differentiated hypertrophic chondrocytes that had lost PPR. Acceleration of periarticular to columnar differentiation was also noted in this mouse, while most of periarticular chondrocytes retained PPR signaling. These data suggest that Ihh positively controls differentiation of periarticular chondrocytes independently of PTHrP. Thus, chondrocyte differentiation is controlled at multiple steps by PTHrP and Ihh through the mutual regulation of their activities.