Spontaneous calcium signaling of cartilage cells: from spatiotemporal features to biophysical modeling

Intracellular calcium ([Ca²⁺]_i) oscillation is a fundamental signaling response of cartilage cells under mechanical loading or osmotic stress. Chondrocytes are usually considered as nonexcitable cells with no spontaneous [Ca²⁺]_i signaling. This study proved that chondrocytes can exhibit robust spontaneous [Ca²⁺]_i signaling without explicit external stimuli. The intensity of [Ca²⁺]_i peaks from individual chondrocytes maintain a consistent spatiotemporal pattern, acting as a unique "fingerprint" for each cell. Statistical analysis revealed lognormal distributions of the temporal parameters of [Ca²⁺]_i peaks, as well as strong linear correlations between their means and sds. Based on these statistical findings, we hypothesized that the spontaneous [Ca²⁺]_i peaks may result from an autocatalytic process and that [Ca²⁺]_i oscillation is controlled by a threshold-regulating mechanism. To test these 2 mechanisms, we established a multistage biophysical model by assuming the spontaneous [Ca²⁺]_i signaling of chondrocytes as a combination of deterministic and stochastic processes. The theoretical model successfully explained the lognormal distribution of the temporal parameters and the fingerprint feature of [Ca²⁺]_i peaks. In addition, by using antagonists for 10 pathways, we revealed that the initiation of spontaneous [Ca²⁺]_i peaks in chondrocytes requires the presence of extracellular Ca²⁺, and that the PLC-inositol 1,4,5-trisphosphate pathway, which controls the release of calcium from the endoplasmic reticulum, can affect the initiation of spontaneous [Ca²⁺]_i peaks in chondrocytes. The purinoceptors and transient receptor potential vanilloid 4 channels on the plasma membrane also play key roles in the spontaneous [Ca²⁺]_i signaling of chondrocytes. In contrast, blocking the T-type or L-type voltage-gated calcium channel promoted the spontaneous calcium signaling. This study represents a systematic effort to understand the features and initiation mechanisms of spontaneous [Ca²⁺]_i signaling in chondrocytes, which are critical for chondrocyte mechanobiology.-Zhou, Y., Lv, M., Li, T., Zhang, T., Duncan, R., Wang, L., Lu, X. L. Spontaneous calcium signaling of cartilage cells: from spatiotemporal features to biophysical modeling.