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Degenerative disc disease (DDD) is associated with intervertebral disc degeneration of spinal instability. Here, we report that the cilia of nucleus pulposus (NP) cells mediate mechanotransduction to maintain anabolic activity in the discs. We found that mechanical stress promotes transport of parathyroid hormone 1 receptor (PTH1R) to the cilia and enhances parathyroid hormone (PTH) signaling in NP cells. PTH induces transcription of integrin α v β 6 to activate the transforming growth factor (TGF)-β-connective tissue growth factor (CCN2)-matrix proteins signaling cascade. Intermittent injection of PTH (iPTH) effectively attenuates disc degeneration of aged mice by direct signaling through NP cells, specifically improving intervertebral disc height and volume by increasing levels of TGF-β activity, CCN2, and aggrecan. PTH1R is expressed in both mouse and human NP cells. Importantly, knockout PTH1R or cilia in the NP cells results in significant disc degeneration and blunts the effect of PTH on attenuation of aged discs. Thus, mechanical stress-induced transport of PTH1R to the cilia enhances PTH signaling, which helps maintain intervertebral disc homeostasis, particularly during aging, indicating therapeutic potential of iPTH for DDD., Competing Interests: The authors declare no competing interests.

A better understanding of functional changes in the intervertebral disc (IVD) and interaction with endplate is essential to elucidate the pathogenesis of IVD degeneration disease (IDDD). To date, the simultaneous depiction of 3D micro-architectural changes of endplate with aging and interaction with IVD remains a technical challenge. We aim to characterize the 3D morphology changes of endplate and IVD during aging using PPCST. The lumbar vertebral level 4/5 IVDs harvested from 15-day-, 4- and 24-month-old mice were initially evaluated by PPCST with histological sections subsequently analyzed to confirm the imaging efficiency. Quantitative assessments of age-related trends after aging, including mean diameter, volume fraction and connectivity of the canals, and endplate porosity and thickness, reached a peak at 4 months and significantly decreased at 24 months. The IVD volume consistently exhibited same trend of variation with the endplate after aging. In this study, PPCST simultaneously provided comprehensive details of 3D morphological changes of the IVD and canal network in the endplate and the interaction after aging. The results suggest that PPCST has the potential to provide a new platform for attaining a deeper insight into the pathogenesis of IDDD, providing potential therapeutic targets.

Benign prostatic hyperplasia (BPH) is the overgrowth of prostate tissues with high prevalence in older men. BPH pathogenesis is not completely understood, but it is believed to be a result of de novo overgrowth of prostatic stroma. In this study, we show that aberrant activation of transforming growth factor-β (TGF-β) mobilizes mesenchymal/stromal stem cells (MSCs) in circulating blood, which are recruited for the prostatic stromal hyperplasia. Elevated levels of active TGF-β were observed in both a phenylephrine-induced prostatic hyperplasia mouse model and human BPH tissues. Nestin lineage tracing revealed that 39.6% ± 6.3% of fibroblasts and 73.3% ± 4.2% smooth muscle cells were derived from nestin + cells in Nestin-Cre, Rosa26-YFP flox/+ mice. Nestin + MSCs were increased in the prostatic hyperplasia mice. Our parabiosis experiment demonstrate that nestin + MSCs were mobilized and recruited to the prostatic stroma of wild-type mice and gave rise to the fibroblasts. Moreover, injection of a TGF-β neutralizing antibody (1D11) inhibits mobilization of MSCs, their recruitment to the prostatic stroma and hyperplasia. Importantly, knockout of TβRII in nestin + cell lineage ameliorated stromal hyperplasia. Thus, elevated levels of TGF-β-induced mobilization and recruitment of MSCs to the reactive stroma resulting in overgrowth of prostate tissues in BPH and, thus, inhibition of TGF-β activity could be a potential therapy for BPH. Stem Cells Translational Medicine 2017;6:394-404., (© 2016 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Osteoarthritis (OA) is a major source of pain and disability worldwide with no effective medical therapy due to poor understanding of its pathogenesis. Transforming growth factor β (TGF-β) has been reported to play a role in subchondral bone pathology and articular cartilage degeneration during the progression of OA. In this study, we demonstrated that systemic use of a TGF-β-neutralizing antibody (1D11) attenuates OA progression by targeting subchondral bone pathological features in rodent OA models. Systemic administration of 1D11 preserves the subchondral bone microarchitecture, preventing articular cartilage degeneration by inhibition of excessive TGF-β activity, in both subchondral bone and the circulation. Moreover, the aberrant increases in the numbers of blood vessels, nestin(+) mesenchymal stromal/stem cells, and osterix(+) osteoblast progenitors were normalized by 1D11 systemic injection. Thus, systemic neutralization of excessive TGF-β ligands effectively prevented OA progression in animal models, with promising clinical implications for OA treatment., (© 2016 New York Academy of Sciences.)