Chondroprotective role of the osmotically sensitive ion channel transient receptor potential vanilloid 4: Age‐ and sex‐dependent progression of osteoarthritis in Trpv4‐deficient mice

Objective

Mechanical loading significantly influences the physiology and pathology of articular cartilage, although the mechanisms of mechanical signal transduction are not fully understood. Transient receptor potential vanilloid 4 (TRPV4) is a Ca⁺⁺‐permeable ion channel that is highly expressed by articular chondrocytes and can be gated by osmotic and mechanical stimuli. The goal of this study was to determine the role of Trpv4 in the structure of the mouse knee joint and to determine whether Trpv4^–/– mice exhibit altered Ca⁺⁺ signaling in response to osmotic challenge.

Methods

Knee joints of Trpv4^–/– mice were examined histologically and by microfocal computed tomography for osteoarthritic changes and bone structure at ages 4, 6, 9, and 12 months. Fluorescence imaging was used to quantify chondrocytic Ca⁺⁺ signaling within intact femoral cartilage in response to osmotic stimuli.

Results

Deletion of Trpv4 resulted in severe osteoarthritic changes, including cartilage fibrillation, eburnation, and loss of proteoglycans, that were dependent on age and male sex. Subchondral bone volume and calcified meniscal volume were greatly increased, again in male mice. Chondrocytes from Trpv4^+/+ mice demonstrated significant Ca⁺⁺ responses to hypo‐osmotic stress but not to hyperosmotic stress. The response to hypo‐osmotic stress or to the TRPV4 agonist 4α‐phorbol 12,13‐didecanoate was eliminated in Trpv4^–/– mice.

Conclusion

Deletion of Trpv4 leads to a lack of osmotically induced Ca⁺⁺ signaling in articular chondrocytes, accompanied by progressive, sex‐dependent increases in bone density and osteoarthritic joint degeneration. These findings suggest a critical role for TRPV4‐mediated Ca⁺⁺ signaling in the maintenance of joint health and normal skeletal structure.

     

Extrinsic energy sources affect hardness through depth during set of a glass-ionomer cement

Objective

To investigate the effect of various energy sources on the upper and lower surface hardness of a setting glass ionomer with various thicknesses.

Method

Cylindrical specimens (4 mm diameter by 1, 2 or 4 mm thickness) of a glass-ionomer cement were prepared with no applied energy source (control), by preheating GIC capsules in a waterbath prior to mixing, application of light with high irradiance or ultrasonic excitation with a scaler tip. The upper and lower surface hardness was measured 0.5 h, 4 h and 1 week following material mixing. The increase in temperature towards the lower surface of each specimen was monitored throughout the first 5 min of setting.

Results

No significant differences in hardness between upper and lower surfaces or varying thicknesses were identified for control and preheated samples at any post-mix time (p > 0.05). At 0.5 h post-mix, the upper surface hardness of preheated, light and ultrasonic treatments was significantly increased compared with that of the control groups. Following 4 h post-mix, the overall hardness of preheated samples was significantly greater (p < 0.001) than other sample groups, which were not statistically different (p = 0.684). No significant differences in hardness between test groups were identified following 1 week (p > 0.05).

Conclusions

Preheating GIC capsules prior to mixing resulted in superior hardness values through depth up to and including 4 h post-mix compared with specimen surfaces treated with light irradiation or with an ultrasonic scaler tip.     

Is there evidence for dual causation between malaria and socioeconomic status? Findings from rural Tanzania

Malaria's relationship with socioeconomic status at the macroeconomic level has been established. This is the first study to explore this relationship at the microeconomic (household) level and estimate the direction of association. Malaria prevalence was measured by parasitemia, and household socioeconomic status was measured using an asset based index. Results from an instrumental variable probit model suggest that socioeconomic status is negatively associated with malaria parasitemia. Other variables that are significantly associated with parasitemia include age of the individual, use of a mosquito net on the night before interview, the number of people living in the household, whether the household was residing at their farm home at the time of interview, household wall construction, and the region of residence. Matching estimators indicate that malaria parasitemia is associated with reduced household socioeconomic status.     

Radiation induced peripheral nerve tumors: <Emphasis Type="Italic">case series and review of the literature</Emphasis>

Purpose Radiation induced peripheral nerve tumors (PNT) are a rare but known complication of radiotherapy. The clinical and pathologic features of six cases of post-radiation PNT’s are reported here, more than doubling the number of known cases reported in the literature. Methods We reviewed six cases of radiation induced PNT and performed a review of the current literature on radiation induced neurofibromas. Results Patient’s ranged in age from 18 months to 49 years at the time of their original diagnosis, with radiation doses to the primary tumor ranging from 24 to 40 Gy with post radiation intervals from 10 to 50 years. The majority of PNT’s identified were neurofibromas (3) and schwannomas (3). Nuclear atypia, S100 positive staining and mild—moderate cellularity were common pathologic findings. Conclusions There are only a handful of neurofibromas in the 60 cases of PNT’s thus far reported. This case series broadens the post-radiation neurofibroma literature. While the pathology of PNT induced transformation is still poorly understood, experiments and pathology are congruent on the possibility of malignant transformation, especially for the “atypical neurofibroma”. On the clinical level, this case series lends its support to some, but not all, of the risk factors thought to predispose to the formation of radiation induced neurofibromas. Though rare, the complication of radiation-induced neurofibroma cannot be ignored, especially with the increasing use of focused radiosurgical techniques.     

Micro-scale and meso-scale architectural cues cooperate and compete to direct aligned tissue formation

Tissue and biomaterial microenvironments provide architectural cues that direct important cell behaviors including cell shape, alignment, migration, and resulting tissue formation. These architectural features may be presented to cells across multiple length scales, from nanometers to millimeters in size. In this study, we examined how architectural cues at two distinctly different length scales, “micro-scale” cues on the order of ∼1–2 μm, and “meso-scale” cues several orders of magnitude larger (>100 μm), interact to direct aligned neo-tissue formation. Utilizing a micro-photopatterning (μPP) model system to precisely arrange cell-adhesive patterns, we examined the effects of substrate architecture at these length scales on human mesenchymal stem cell (hMSC) organization, gene expression, and fibrillar collagen deposition. Both micro- and meso-scale architectures directed cell alignment and resulting tissue organization, and when combined, meso cues could enhance or compete against micro-scale cues. As meso boundary aspect ratios were increased, meso-scale cues overrode micro-scale cues and controlled tissue alignment, with a characteristic critical width (∼500 μm) similar to boundary dimensions that exist in vivo in highly aligned tissues. Meso-scale cues acted via both lateral confinement (in a cell-density-dependent manner) and by permitting end-to-end cell arrangements that yielded greater fibrillar collagen deposition. Despite large differences in fibrillar collagen content and organization between μPP architectural conditions, these changes did not correspond with changes in gene expression of key matrix or tendon-related genes. These findings highlight the complex interplay between geometric cues at multiple length scales and may have implications for tissue engineering strategies, where scaffold designs that incorporate cues at multiple length scales could improve neo-tissue organization and resulting functional outcomes.