Small Leucine-Rich Proteoglycans in Kidney Disease

Small leucine-rich proteoglycans orchestrate receptor crosstalk during inflammation

“…Upon tissue stress or injury, matrix components will be released and turn into signaling molecules. 12,18,19 Among this large group of ECM components, only a few, such as biglycan, 14 decorin, 16 hyaluronan, 20 versican, 21 tenascin-C, 22 fibrinogen and heparan sulfate fragments, 23 are capable of interacting with PRRs, thereby alerting the innate immune system to impending tissue damage. These mechanisms give rise to a rapid response reaction without the need for de novo synthesis of danger molecules.…”

“…The finding that decorin, besides being a structural matrix component, acts as a signaling molecule gave rise to a new paradigm of how SLRPs regulate a host of biologic processes, such as differentiation, proliferation, migration and apoptosis. Decorin is capable of binding to four different receptor tyrosine kinases (RTKs), including the epidermal growth factor receptor (EGFR), 34 insulin-like growth factor-1 receptor (IGF-IR), [35][36][37][38] Met 39 and vascular endothelial growth factor receptor 2 (VEGFR2), 40 thereby impacting on fibrogenesis, 19 tumor growth and metastatic spreading. 12,41,42 A summary of recent data demonstrating the intricacy of decorin signaling, which links innate immunity, inflammation and tumor growth 16 is provided below.…”

“…14 Upon tissue stress or injury, biglycan becomes proteolytically released from the matrix to signal impending danger to the immune system. 19 Several proteolytic enzymes, such as bone morphogenic protein (BMP)-1, matrix metalloproteinase (MMP)-2, MMP-3 and MMP-13 have been described to cleave the biglycan protein core. [48][49][50][51] In its soluble form, intact biglycan expression and active caspase-1.…”

“…[54][55][56] The correlation between enhanced abundance of biglycan and reduction of organ function in various sterile inflammatory renal diseases has been particularly well documented. 8,19,[55][56][57][58] Upregulation of biglycan in aortic stenosis, characterized by lipid accumulation and inflammation, 59 results in enhanced synthesis of phospholipid transfer protein via stimulation of TLR2. 60 Furthermore, higher levels of biglycan in cardiac transplant coronary arteriopathy, 58 severe ocular surface disease 61 and in adipose tissue 62 suggest a role for biglycan in the perpetuation of inflammation.…”

Axonally derived matrilin-2 induces proinflammatory responses that exacerbate autoimmune neuroinflammation

“…DAMPs comprise endogenous molecules that are released following tissue injury and signal the innate immune system to initiate and maintain inflammatory responses (14)(15)(16). DAMPs are normally sequestered intracellularly or are bound tightly in the ECM and can only become active signaling molecules following release after cell damage or ECM degradation.…”