SPARC

SPARC works through several pathways. For ECM remodeling, SPARC binds collagen and growth factors IGF-1 and TGF-β1. SPARC activation of ILK-GSK3β-β-catenin signaling promotes tissue integrity. By binding TGF-β1 co-receptor, SPARC also inhibits TGF-β1 signaling. Blocking the TGF-β1-Smad3-atrogin-1 pathway prevents the proteolytic degradation of the myogenic transcription factors MyoD and myogenin, thus enhancing muscle differentiation and preventing degradation (atrogin).
For mitochondrial biogenesis, SPARC binds AMPK and causes activation of PGC1α. This activates the ILK-GSK3β-PGC1α pathway which induces NRF1. NRF1 then leads to increased expression of OXPHOS, increased glucose metabolism through GLUT4 upregulation, and increased insulin sensitivity. SPARC downregulates inflammation through effects on monocyte/macrophage activity with TGF-β1 by decreasing inflammatory mediators such as IL-6 and CRP. Finally, SPARC inhibits adipocyte differentiation, preventing diet-induced obesity and white fat browning.

Fig. 1 Possible mechanisms linking extracellular matrix (ECM), mitochondrial biogenesis, the effects of SPARC and exercise training. (Man J, et al. 2023)

Malignant glioma is one of the most lethal and common brain tumors and patients survive 15 months on average. Current chemotherapies have low tolerance and poor BBB permeability, thus the concentration of administered drug cannot reach the desired levels at the tumor site which leads to a lack of effect. To address this problem, scientists created a precise photodynamic tumor therapy with a photosensitizer (ZnPcS) that can bind albumin in situ. Albumin-binding ZnPcS could penetrate the BBB increasing its permeability and specifically target glioma. ZnPcS that binds to albumin was created to pass through the BBB and bind to secreted protein acidic and rich in cysteine (SPARC), which is highly expressed in glioma plasma membrane. When the upper region of mice brain was exposed to laser light (0.2 W cm−2) after glioma transplantation and intravenous injection of ZnPcS, tumor growth decreased by approximately 83.6% and the survival rate of the treated group had a 14-day increase over the control group. When SPARC was knocked out of glioma, there was a 63.1% decrease in ZnPcS that entered the glioma indicating targeting can occur through the SPARC pathway. This demonstrated albumin-binding photosensitizer could be useful in treating malignant gliomas.

Fig. 2 Albumin-binding ZnPcS is capable of targeting glioma via the SPARC pathway. (Li X, et al. 2023)