Proliferative behaviours of CD90-expressing chondrocytes under the control of the TSC1-mTOR/PTHrP-nuclear localisation segment pathway

  • Osteoarthritis Cartilage. 2024 Dec 25:S1063-4584(24)01507-3. doi: 10.1016/j.joca.2024.11.011.
Lingfeng Xu  1 ,  Yuejiao Zhang  2 ,  Hongxu Yang  1 ,  Qian Liu  3 ,  Peinan Fan  1 ,  Jia Yu  1 ,  Mian Zhang  1 ,  Shibin Yu  1 ,  Yaoping Wu  4 ,  Meiqing Wang  5
Affiliations
  • 1. Department of Oral Anatomy and Physiology and TMD, College of Stomatology, the Fourth Military Medical University, Xi'an, China.
  • 2. Department of Oral Anatomy and Physiology and TMD, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, China.
  • 3. Department of Stomatology, Air Force Medical Center, PLA, The Fourth Military Medical University, Beijing, China.
  • 4. Department of Joint Surgery, Shenzhen Hospital of Southern Medical University, Shenzhen, China. Electronic address: [email protected].
  • 5. Department of Oral Anatomy and Physiology and TMD, College of Stomatology, the Fourth Military Medical University, Xi'an, China; Department of Oral Anatomy and Physiology and TMD, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, China. Electronic address: [email protected].
PMID: 39730094 DOI: 10.1016/j.joca.2024.11.011
Abstract

Objective: Some cells in temporomandibular joint (TMJ) cartilage undergo proliferation in response to negative pressure, which can be induced in vivo by creating bilateral anterior elevation (BAE). TMJ cartilage harbours CD90-expressing cells, and CD90 expression increases under certain controlled conditions. The parathyroid hormone-related peptide (PTHrP) nuclear localisation segment (NLS) promotes chondrocyte proliferation, and mammalian target of rapamycin (mTOR) signalling plays a regulatory role in promoting PTHrP transcription. The purpose of this study was to determine the role of the mTOR/PTHrP-NLS axis in the proliferative responses of CD90+ chondrocytes in TMJ cartilage to BAE.

Methods: CD90+ cells were isolated from TMJ cartilage and subjected to negative pressure followed by RNA Sequencing (RNA-seq). A PTHrP-NLS conditional mutation (CD90-CreER;Pthlh84STOP-fl/fl) mouse model was developed to obtain CD90+ cell-specific PTHrP-NLS conditional mutation (Pthlh84STOP) littermate. CD90-Cre;Tsc1fl/fl mice and CD90-Cre;mTORfl/fl mice were generated to obtain mTOR conditional knockout (Mtor-CKO) and Tsc1-CKO littermates.

Results: Using RNA-seq, the mTOR signalling pathway was identified as the most significant biological process occurring in superficial zone cells of the TMJ condylar cartilage under negative pressure. Proliferation of CD90+ cells was stimulated in Tsc1-CKO littermates but inhibited in both Mtor-CKO and Pthlh84STOP littermates. BAE did not promote chondrocyte proliferation in either Mtor-CKO or Pthlh84STOP littermates. Administration of the PTHrP87-139 peptide to Mtor-CKO mice restored chondrocyte proliferation and rescued the promoting effect of BAE in TMJ cartilage.

Conclusions: CD90+ chondrocytes in TMJ cartilage proliferate in response to negative pressure under the control of the TSC1-mTOR/PTHrP-NLS pathway.

Keywords
Cartilage; Cell proliferation; Chondrocytes; Mechanistic target of rapamycin complex 1; Parathyroid hormone-related protein; Temporomandibular joint (TMJ).
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