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

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 localization 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;Pthlh^84STOP-fl/fl) mouse model was developed to obtain CD90⁺ cell-specific PTHrP-NLS conditional mutation (Pthlh^84STOP) littermate. CD90-Cre;Tsc1^fl/fl mice and CD90-Cre;mTOR^fl/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 Pthlh^84STOP littermates. BAE did not promote chondrocyte proliferation in either Mtor-CKO or Pthlh^84STOP littermates. Administration of the PTHrP_87-139 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.