MMP-13 is constitutively produced in human chondrocytes and co-endocytosed with ADAMTS-5 and TIMP-3 by the endocytic receptor LRP1

Matrix protease activity is fundamental to developmental tissue patterning and remains influential in adult homeostasis. In cartilage, the principal matrix proteoglycan is aggrecan, the protease-mediated catabolism of which defines arthritis; however, the pathophysiologic mechanisms that drive aberrant aggrecanolytic activity remain unclear. Human ciliopathies exhibit altered matrix, which has been proposed to be the result of dysregulated hedgehog signaling that is tuned within the primary cilium. Here, we report that disruption of intraflagellar transport protein 88 (IFT88), a core ciliary trafficking protein, increases chondrocyte aggrecanase activity in vitro. We find that the receptor for protease endocytosis in chondrocytes, LDL receptor–related protein 1 (LRP-1), is unevenly distributed over the cell membrane, often concentrated at the site of cilia assembly. Hypomorphic mutation of IFT88 disturbs this apparent hot spot for protease uptake, increases receptor shedding, and results in a reduced rate of protease clearance from the extracellular space. We propose that IFT88 and/or the cilium regulates the extracellular remodeling of matrix—independently of Hedgehog regulation—by enabling rapid LRP-1–mediated endocytosis of proteases, potentially by supporting the creation of a ciliary pocket. This result highlights new roles for the cilium’s machinery in matrix turnover and LRP-1 function, with potential relevance in a range of diseases.—Coveney, C. R., Collins, I., Mc Fie, M., Chanalaris, A., Yamamoto, K., Wann, A. K. T. Cilia protein IFT88 regulates extracellular protease activity by optimizing LRP-1–mediated endocytosis.

show abstract

“…(42), and recombinant MMP-13 is described in Yamamoto et al . (43). Recombinant IL-1β was purchased from PeproTech (London, United Kingdom).…”

Section: Methodsmentioning

confidence: 99%

Cilia protein IFT88 regulates extracellular protease activity by optimizing LRP‐1–mediated endocytosis

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…Under normal circumstances, MMP-13 is constitutively produced in human chondrocytes, but is rapidly endocytosed and degraded [203, 204]. MMP-13 is specifically expressed in the cartilage of human OA patients and is not present in normal cartilage.…”

Section: The Role Of Collagen Catabolism In Diseasementioning

confidence: 99%

Matrix metalloproteinase collagenolysis in health and disease

Amar

Smith

Fields

2017

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

167

108

View full text Add to dashboard Cite

The proteolytic processing of collagen (collagenolysis) is critical in development and homeostasis, but also contributes to numerous pathologies. Mammalian interstitial collagenolytic enzymes include members of the matrix metalloproteinase (MMP) family and cathepsin K. While MMPs have long been recognized for their ability to catalyze the hydrolysis of collagen, the roles of individual MMPs in physiological and pathological collagenolysis are less defined. The use of knockout and mutant animal models, which reflect human diseases, has revealed distinct collagenolytic roles for MT1-MMP and MMP-13. A better understanding of temporal and spatial collagen processing, along with the knowledge of the specific MMP involved, will ultimately lead to more effective treatments for cancer, arthritis, cardiovascular conditions, and infectious diseases.

show abstract

“…Endocytosis of MT4-MMP proceeds by neither pathway, but rather through early endosomes via the pathway of clathrin-independent carriers/GPI-enriched early endosomal compartments [84]. Soluble MMP-13 is rapidly endocytosed by association of its HPX domain with LRP-1 [87]. How other soluble MMPs undergo endocytosis will require investigation.…”

Section: Influences Of Peripheral Membrane Interactions On Mmp Actmentioning

confidence: 99%

Peripheral membrane associations of matrix metalloproteinases

Doren

Marcink

Koppisetti

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

View full text Add to dashboard Cite

Water soluble matrix metalloproteinases (MMPs) have been regarded as diffusing freely in the extracellular matrix. Yet multiple MMPs are also observed at cell surfaces. Their membrane-proximal activities include sheddase activities, collagenolysis, bacterial killing, and intracellular trafficking reaching as far as the nucleus. The catalytic domains of MMP-7 and MMP-12 bind bilayers peripherally, each in two different orientations, by presenting positive charges and a few hydrophobic groups to the surface. Related peripheral membrane associations are predicted for other soluble MMPs. The peripheral membrane associations may support pericellular proteolysis and endocytosis. The isolated soluble domains of MT1-MMP can also associate with membranes. NMR assays suggest transient association of the hemopexin-like domains of MT1-MMP and MMP-12 with lipid bilayers. Peripheral association of soluble MMP domains with bilayers or heparin sulfate proteoglycans probably concentrates them near the membrane. This could increase the probability of forming complexes with membrane-associated proteins, such as those targeted for proteolysis.

show abstract

MMP-13 is constitutively produced in human chondrocytes and co-endocytosed with ADAMTS-5 and TIMP-3 by the endocytic receptor LRP1

Cited by 142 publications

References 72 publications

Cilia protein IFT88 regulates extracellular protease activity by optimizing LRP‐1–mediated endocytosis

Cilia protein IFT88 regulates extracellular protease activity by optimizing LRP‐1–mediated endocytosis

Matrix metalloproteinase collagenolysis in health and disease

Peripheral membrane associations of matrix metalloproteinases

Contact Info

Product

Resources

About