The chondrocyte "mechanome": Activation of the mechanosensitive ion channels TRPV4 and PIEZO1 drives unique transcriptional signatures.

The mechanosensitive ion channels Transient Receptor Potential Vanilloid 4 (TRPV4) and PIEZO1 transduce physiologic and supraphysiologic magnitudes of mechanical signals in the chondrocyte, respectively. TRPV4 activation promotes chondrogenesis, while PIEZO1 activation by supraphysiologic deformations drives cell death. The mechanisms by which activation of these channels discretely drives changes in gene expression to alter cell behavior remain to be determined. To date, no studies have contrasted the transcriptomic response to activation of these channels nor has any published data attempted to correlate these transcriptomes to alterations in cellular function. This study used RNA sequencing to comprehensively investigate the transcriptomes associated with activation of TRPV4 or PIEZO1, revealing that TRPV4 and PIEZO drive distinct transcriptomes and also exhibit unique co-regulated clusters of genes. Notably, activation of PIEZO1 through supraphysiologic deformation induced a transient inflammatory profile that overlapped with the interleukin (IL)-1-responsive transcriptome and contained genes associated with cartilage degradation and osteoarthritis progression. However, both TRPV4 and PIEZO1 were also shown to elicit anabolic effects. PIEZO1 expression promoted a pro-chondrogenic transcriptome under unloaded conditions, and daily treatment with PIEZO1 agonist Yoda1 significantly increased sulfated glycosaminoglycan deposition in vitro. These findings emphasize the presence of a broad "mechanome" with distinct effects of TRPV4 and PIEZO1 activation in chondrocytes, suggesting complex roles for PIEZO1 in both the physiologic and pathologic responses of chondrocytes. The identification of transcriptomic profiles unique to or shared by PIEZO1 and TRPV4 (distinct from IL-1-induced inflammation) could inform future therapeutic designs targeting these channels for the management and treatment of osteoarthritis.

Will you go the distance? A satisfaction survey of telemedicine in sexual medicine.

Background: The success of telemedicine depends on patient satisfaction with the care that they receive, which is impacted by the ease of use of the technology, quality of the connection, and perceived effectiveness of care. Aim: The study sought to evaluate patient satisfaction with telemedicine services in a high-volume andrology clinic. Methods: We included all patients who had a telemedicine appointment between January 1, 2020, and August 22, 2022. Demographic information was gathered, and a satisfaction survey was conducted using REDCap software. Data were grouped into 2 age categories, with ≥50 years as the cutoff (19-50 years; >50 years). The data were analyzed according to age, distance from the patient's home to our center, and survey responses. Pearson's chi-square test and ordinal logistic regression analyses were performed. Outcomes: The main outcome is satisfaction with telemedicine in a men's sexual health context. Results: A total of 4071 patients were identified based on attending a telemedicine visit. Hypogonadism was the most common diagnosis. Other diagnoses included erectile dysfunction, varicocele, Peyronie's disease, vasectomy, and infertility. In total, 613 patients completed the survey, with a mean age of 56.6 years. Older patients were less likely to prefer telemedicine (odds ratio [OR], 0.55; 95% confidence interval [CI], 0.36-0.80; P < .001), less likely to agree to a video visit because of privacy concerns (OR, 0.51; 95% CI, 0.35-0.75; P < .001), and less likely to recommend a telemedicine visit compared with their younger counterparts (OR, 0.37; 95% CI, 0.27-0.51; P < .001). The median distance was 22.4 (interquartile range, 7.5-57.5) miles. However, there was no significant association between distance and patients' likelihood of preferring telehealth visits, including reviews of outside laboratories and imaging (OR, 1; 95% CI, 0.99-1; P = .35), belief in the quality of care provided via video visits (OR, 0.99, CI 0.99-1; P = .25), and overall preference for telehealth visits (OR, 0.99; 95% CI, 0.99-1; P = .35). Clinical Implications: Healthcare providers should consider the age of patients when deciding to offer telemedicine while addressing privacy concerns to provide adequate reassurance to patients who may have concerns about the quality of care provided through telemedicine. Strengths and Limitations: Our study achieved a substantial sample size that reached statistical significance. Conducted at a single academic center, our study was constrained, possibly introducing biases related to the institution's advanced telemedicine system. Geographic and diagnostic limitations could lead to regional biases, affecting the generalizability of the findings. Conclusion: Older patients exhibited a lower inclination toward preferring telemedicine, along with decreased odds of endorsing in-person visits.

A synthetic mechanogenetic gene circuit for autonomous drug delivery in engineered tissues.

Mechanobiologic signals regulate cellular responses under physiologic and pathologic conditions. Using synthetic biology and tissue engineering, we developed a mechanically responsive bioartificial tissue that responds to mechanical loading to produce a preprogrammed therapeutic biologic drug. By deconstructing the signaling networks induced by activation of the mechanically sensitive ion channel transient receptor potential vanilloid 4 (TRPV4), we created synthetic TRPV4-responsive genetic circuits in chondrocytes. We engineered these cells into living tissues that respond to mechanical loading by producing the anti-inflammatory biologic drug interleukin-1 receptor antagonist. Chondrocyte TRPV4 is activated by osmotic loading and not by direct cellular deformation, suggesting that tissue loading is transduced into an osmotic signal that activates TRPV4. Either osmotic or mechanical loading of tissues transduced with TRPV4-responsive circuits protected constructs from inflammatory degradation by interleukin-1α. This synthetic mechanobiology approach was used to develop a mechanogenetic system to enable long-term, autonomously regulated drug delivery driven by physiologically relevant loading.