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

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 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;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.