Mesenchymal stem cells (MSCs), due to their multilineage differentiation potential, represent a promising cell source for cartilage and bone regeneration, while bone morphogenetic protein 2 (BMP2) has been recognized as a potent inducer of chondrogenic and osteogenic differentiation. However, BMP2-driven cartilage formation is frequently accompanied by hypertrophic maturation and subsequent ossification, limiting its application in cartilage tissue engineering. Although parathyroid hormone-related protein (PTHrP), a critical regulator of skeletal development and endochondral ossification, has been implicated in maintaining chondrocyte proliferation and preventing premature hypertrophy, its precise role and the underlying mechanisms governing BMP2-induced osteochondral differentiation of MSCs remain poorly understood.

To address this question, a recent study published in Genes & Diseases by researchers from The First Affiliated Hospital of Chongqing Medical University, The University of Chicago, and The Second People's Hospital of Chongqing Yubei District delineates the specific role of PTHrP in BMP2-induced chondral-osteogenic and hypertrophic differentiation.

Using adenoviral-mediated overexpression and silencing of PTHrP in BMP2-stimulated MSCs, the authors demonstrated that endogenous PTHrP is essential for efficient osteochondral differentiation, as PTHrP depletion markedly reduced chondrogenic differentiation, extracellular matrix (ECM) production, and subsequent osteogenic maturation. Conversely, overexpression of PTHrP enhanced early chondrogenic differentiation while preventing its transition to hypertrophic cartilage, suggesting that PTHrP redirects BMP2-induced differentiation toward a more stable cartilaginous phenotype rather than suppressing differentiation altogether.

Functional analyses further revealed that PTHrP selectively modulates the progression of osteochondral maturation. Histological evaluation together with Safranin O/Fast Green staining demonstrated that BMP2 induced robust cartilage formation accompanied by early trabecular bone development, consistent with endochondral ossification. In contrast, PTHrP overexpression maintained the implanted tissues predominantly in a cartilaginous state and substantially delayed trabecular bone formation, whereas silencing PTHrP diminished both cartilage formation and osteogenic differentiation. Quantitative assessment of cartilage matrix production confirmed increased ECM deposition in the presence of exogenous PTHrP, while immunohistochemical analyses further demonstrated enhanced expression of the chondrogenic marker Col2a1 with concomitant suppression of the osteogenic transcription factor Runx2, indicating sustained preservation of cartilage identity during BMP2-induced differentiation.

In vivo studies further established that PTHrP not only delayed endochondral ossification but also prolonged the maintenance of the cartilage phenotype throughout tissue maturation. Microstructural and histological analyses showed that BMP2-treated MSCs progressively developed mature trabecular bone over time, whereas PTHrP-overexpressing constructs retained abundant cartilage tissue even at later stages. These observations establish PTHrP as a critical regulator that balances cartilage formation and ossification, ensuring prolonged cartilage stability without abolishing the regenerative effects of BMP2.

Mechanistically, BMP2 stimulated the expression of the master chondrogenic regulator Sox9 together with the hypertrophic marker Runx2. Overexpression of PTHrP selectively enhanced Sox9 expression with only a modest effect on Runx2, whereas silencing endogenous PTHrP significantly attenuated BMP2-induced Sox9 expression and impaired osteochondral differentiation. Further investigation identified inactivation of the PI3K–AKT signaling pathway as the central mechanism underlying these effects, demonstrating that suppression of PI3K–AKT signaling by PTHrP inhibits hypertrophic maturation while maintaining the chondrogenic phenotype.

In conclusion, by inactivating the PI3K–AKT signaling pathway, PTHrP promotes chondrogenesis while inhibiting hypertrophic differentiation, suggesting its potential application in BMP2-based cartilage tissue engineering.

Reference

Title of the original paper: PTHrP suppresses BMP2-induced osteochondral differentiation and preserves cartilage phenotype in mesenchymal stem cells via inactivating PI3K–AKT signaling
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2026.102273

Funding Information:
National Natural Science Foundation of China (No. 81972069)
Natural Science Foundation of Chongqing Science and Technology Commission (China) (No. CSTB2022NSCQ-MSX0814, CSTB2024NSCQ-KJFZZDX0024)
Science and Technology Research Program of Chongqing Municipal Education Commission (China) (No. KJZD-K202500402)
CQMU Program for Youth Innovation in Future Medicine (Chongqing, China) (No. W0154)
Innovation Project from Chongqing Municipal Education Commission (China) (No. CYB21169, CYS20192)
"Qiande" Talent Program–Outstanding Youth of The First Affiliated Hospital of Chongqing Medical University (Chongqing, China)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

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