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Peer-reviewedCC BY-NCScience Advances

p75 NTR orchestrates chondrogenesis and mechanoadaptation to preserve temporomandibular joint development and homeostasis

  • Chiho Kadota-Watanabe1,2,3
  • Jinsook Suh1
  • Eric Yin1
  • Byron Zhao1
  • Jey Kim1
  • Yan Zhang1
  • In-Won Chang4
  • Sowmya Ramesh5
  • Yuna Lee1
  • Joshua Chen1
  • Maulik Ahuja1
  • Sara Jahangiri1
14 more authors
  • Isabelle Lao-Ngo1
  • Ursula Eisinger1
  • Kate Lindsey1
  • Haihui Zhang1
  • Fatemeh Momen-Heravi1,6
  • Juan Du7
  • James M. Gardner7
  • Rebeka Silva8
  • Sumit Yadav9
  • Chelsea S. Bahney3,10
  • Aaron W. James5
  • Reuben H. Kim4
  • Ophir D. Klein1,11
  • Christine Hong1,12
12 affiliations
  1. 1Department of Orofacial Sciences, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA.
  2. 2Department of Maxillofacial Orthognathics, Division of Maxillofacial and Neck Reconstruction, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan.
  3. 3Orthopaedic Trauma Institute, University of California, San Francisco, San Francisco, CA, USA.
  4. 4The Shapiro Family Laboratory of Viral Oncology and Aging Research, School of Dentistry, University of California, Los Angeles, Los Angeles, CA, USA.
  5. 5Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.
  6. 6Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
  7. 7Department of Surgery, UCSF Diabetes Center, University of California, San Francisco, San Francisco, CA, USA.
  8. 8Oral and Maxillofacial Surgery, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA.
  9. 9Department of Growth and Development, University of Nebraska Medical Center, Omaha, NE, USA.
  10. 10Center for Regenerative Medicine, Steadman Philippon Research Institute, Vail, CO, USA.
  11. 11Department of Pediatrics, Cedars-Sinai Guerin Children’s, Los Angeles, CA, USA.
  12. 12Department of Orthodontics, School of Dentistry, University of Washington, Seattle, WA, USA.
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Abstract

The temporomandibular joint (TMJ) is essential for oral functions such as chewing, speaking, and swallowing. Temporomandibular disorders that impair these functions notably reduce patients' quality of life, and few therapeutic strategies are available to ameliorate these conditions. Here, we identify the neurotrophin receptor (p75NTR) as a central regulator of mandibular condylar cartilage development, mechanoadaptation, and homeostasis. p75NTR loss causes condylar and disc hypoplasia, reduced chondrocyte number, impaired load-induced anabolism, and accelerated degeneration. Conditional deletion experiments demonstrate chondrocyte-autonomous requirements for the brain-derived neurotrophic factor (BDNF)-p75NTR axis, which activates phosphoinositide 3-kinase AKT serine/threonine kinase and p38 mitogen-activated protein kinase signaling to promote proliferation and chondrogenic differentiation while restraining apoptosis. Degenerative human condyles exhibit reduced p75NTR expression levels. Together, these data establish p75NTR as a molecular hub integrating neurotrophic and mechanical cues to preserve postnatal TMJ architecture and highlight the BDNF-p75NTR axis as a potential therapeutic target.

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Cite

BibTeXRIS
BibTeX
@article{kadotawatanabe2026orchestrates,
  title = {{p75 NTR orchestrates chondrogenesis and mechanoadaptation to preserve temporomandibular joint development and homeostasis}},
  author = {Chiho Kadota-Watanabe and Jinsook Suh and Eric Yin and Byron Zhao and Jey Kim and Yan Zhang and In-Won Chang and Sowmya Ramesh and Yuna Lee and Joshua Chen and Maulik Ahuja and Sara Jahangiri and Isabelle Lao-Ngo and Ursula Eisinger and Kate Lindsey and Haihui Zhang and Fatemeh Momen-Heravi and Juan Du and James M. Gardner and Rebeka Silva and Sumit Yadav and Chelsea S. Bahney and Aaron W. James and Reuben H. Kim and Ophir D. Klein and Christine Hong},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.aef7786},
  url = {https://www.science.org/doi/10.1126/sciadv.aef7786},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - p75 NTR orchestrates chondrogenesis and mechanoadaptation to preserve temporomandibular joint development and homeostasis
AU  - Chiho Kadota-Watanabe
AU  - Jinsook Suh
AU  - Eric Yin
AU  - Byron Zhao
AU  - Jey Kim
AU  - Yan Zhang
AU  - In-Won Chang
AU  - Sowmya Ramesh
AU  - Yuna Lee
AU  - Joshua Chen
AU  - Maulik Ahuja
AU  - Sara Jahangiri
AU  - Isabelle Lao-Ngo
AU  - Ursula Eisinger
AU  - Kate Lindsey
AU  - Haihui Zhang
AU  - Fatemeh Momen-Heravi
AU  - Juan Du
AU  - James M. Gardner
AU  - Rebeka Silva
AU  - Sumit Yadav
AU  - Chelsea S. Bahney
AU  - Aaron W. James
AU  - Reuben H. Kim
AU  - Ophir D. Klein
AU  - Christine Hong
PY  - 2026
DA  - 2026/10/21
JO  - Science Advances
DO  - 10.1126/sciadv.aef7786
UR  - https://www.science.org/doi/10.1126/sciadv.aef7786
AB  - The temporomandibular joint (TMJ) is essential for oral functions such as chewing, speaking, and swallowing. Temporomandibular disorders that impair these functions notably reduce patients' quality of life, and few therapeutic strategies are available to ameliorate these conditions. Here, we identify the neurotrophin receptor (p75NTR) as a central regulator of mandibular condylar cartilage development, mechanoadaptation, and homeostasis. p75NTR loss causes condylar and disc hypoplasia, reduced chondrocyte number, impaired load-induced anabolism, and accelerated degeneration. Conditional deletion experiments demonstrate chondrocyte-autonomous requirements for the brain-derived neurotrophic factor (BDNF)-p75NTR axis, which activates phosphoinositide 3-kinase AKT serine/threonine kinase and p38 mitogen-activated protein kinase signaling to promote proliferation and chondrogenic differentiation while restraining apoptosis. Degenerative human condyles exhibit reduced p75NTR expression levels. Together, these data establish p75NTR as a molecular hub integrating neurotrophic and mechanical cues to preserve postnatal TMJ architecture and highlight the BDNF-p75NTR axis as a potential therapeutic target.
SN  - 2375-2548
ER  -