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The metalloproteinase-proteoglycans ADAMTS7 and ADAMTS12 provide an innate, tendon-specific protective mechanism against heterotopic ossification
Timothy J. Mead, … , David E. Birk, Suneel S. Apte
Timothy J. Mead, … , David E. Birk, Suneel S. Apte
Published April 5, 2018
Citation Information: JCI Insight. 2018;3(7):e92941. https://doi.org/10.1172/jci.insight.92941.
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Research Article Bone biology Genetics

The metalloproteinase-proteoglycans ADAMTS7 and ADAMTS12 provide an innate, tendon-specific protective mechanism against heterotopic ossification

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Abstract

Heterotopic ossification (HO) is a significant clinical problem with incompletely resolved mechanisms. Here, the secreted metalloproteinases ADAMTS7 and ADAMTS12 are shown to comprise a unique proteoglycan class that protects against a tendency toward HO in mouse hindlimb tendons, menisci, and ligaments. Adamts7 and Adamts12 mRNAs were sparsely expressed in murine forelimbs but strongly coexpressed in hindlimb tendons, skeletal muscle, ligaments, and meniscal fibrocartilage. Adamts7–/– Adamts12–/– mice, but not corresponding single-gene mutants, which demonstrated compensatory upregulation of the intact homolog mRNA, developed progressive HO in these tissues after 4 months of age. Adamts7–/– Adamts12–/– tendons had abnormal collagen fibrils, accompanied by reduced levels of the small leucine-rich proteoglycans (SLRPs) biglycan, fibromodulin, and decorin, which regulate collagen fibrillogenesis. Bgn–/0 Fmod–/– mice are known to have a strikingly similar hindlimb HO to that of Adamts7–/– Adamts12–/– mice, implicating fibromodulin and biglycan reduction as a likely mechanism underlying HO in Adamts7–/– Adamts12–/– mice. Interestingly, degenerated human biceps tendons had reduced ADAMTS7 mRNA compared with healthy biceps tendons, which expressed both ADAMTS7 and ADAMTS12. These results suggest that ADAMTS7 and ADAMTS12 drive an innate pathway protective against hindlimb HO in mice and may be essential for human tendon health.

Authors

Timothy J. Mead, Daniel R. McCulloch, Jason C. Ho, Yaoyao Du, Sheila M. Adams, David E. Birk, Suneel S. Apte

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Figure 1

ADAMTS12 is an evolutionarily conserved chondroitin sulfate/dermatan sulfate proteoglycan.

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ADAMTS12 is an evolutionarily conserved chondroitin sulfate/dermatan su...
(A) Schematic of ADAMTS12 domain structure. TSR, thrombospondin type 1 repeat; CS, chondroitin sulfate. (B) Alignment of human and mouse ADAMTS12 mucin modules showing a high degree of conservation (asterisks show identical residues, residue numbers are shown on the right), potential N-glycosylation sites (bold) and Ser-Gly dipeptide motifs (red) with acidic neighbors, constituting putative glycosaminoglycan attachment sites. (C) Sequence of the corresponding module from the Ciona intestinalis ortholog of ADAMTS7 and ADAMTS12. Sequence motifs for N-glycosylation (bold) and Ser-Gly/Gly-Ser dipeptides (red) are shown. (D) Representative Western blot (anti-FLAG) of conditioned medium from transiently transfected HEK293F cells shows increased ADAMTS12 band intensity (arrows) following digestion with chondroitinase ABC (C’ABC), but not heparanase or keratanase I & II. The blot is representative of n = 3. (E) Mutation of Ser1157 and Ser1159 (boxed residues in panel B), but not Ser1157 alone eliminates enhanced signal after C’ABC digestion and reactivity to an anti–chondroitin sulfate stub antibody (MAB2035) strongly suggestive of chondroitin/dermatan sulfate attachment at Ser1157 and Ser1159. EV, empty vector; WT, wild type.

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