Postnatal expression in hyaline cartilage of constitutively active human collagenase-3 (MMP-13) induces osteoarthritis in mice
Lisa A. Neuhold, … , Philip Babij, Louis J. DeGennaro
Lisa A. Neuhold, … , Philip Babij, Louis J. DeGennaro
Published January 1, 2001
Citation Information: J Clin Invest. 2001;107(1):35-44. https://doi.org/10.1172/JCI10564.
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Article

Postnatal expression in hyaline cartilage of constitutively active human collagenase-3 (MMP-13) induces osteoarthritis in mice

Abstract

It has been suggested that increased collagenase-3 (MMP-13) activity plays a pivotal role in the pathogenesis of osteoarthritis (OA). We have used tetracycline-regulated transcription in conjunction with a cartilage-specific promoter to target a constitutively active human MMP-13 to the hyaline cartilages and joints of transgenic mice. Postnatal expression of this transgene resulted in pathological changes in articular cartilage of the mouse joints similar to those observed in human OA. These included characteristic erosion of the articular cartilage associated with loss of proteoglycan and excessive cleavage of type II collagen by collagenase, as well as synovial hyperplasia. These results demonstrate that excessive MMP-13 activity can result in articular cartilage degradation and joint pathology of the kind observed in OA, suggesting that excessive activity of this proteinase can lead to this disease.

Authors

Lisa A. Neuhold, Loran Killar, Weiguang Zhao, Mei-Li A. Sung, Linda Warner, John Kulik, James Turner, William Wu, C. Billinghurst, T. Meijers, A. Robin Poole, Philip Babij, Louis J. DeGennaro

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Expression profile of the tTA and MMP-13* RNA by RT-PCR. (a) Amplificati...
Expression profile of the tTA and MMP-13* RNA by RT-PCR. (a) Amplification of MMP13* in each of the transgenic lines. Lane 1: φx174 Hae III MW markers; lane 2: PCR amplification of transgenic (line 6) genomic DNA; lane 3: PCR amplification of nontransgenic genomic DNA; lane 4: a wild-type mouse maintained on Dox; lane 5: a wild-type mouse off Dox; lanes 6–7, 8–9, 10–11, and 12–13: heterozygous lines 6, 8, 42, and 99 (4 weeks) removed from Dox at birth, respectively (duplicate). (b and c) Amplification of tTA (b) and MMP-13* (c) cDNA from total RNA. Lanes 1–5: same as in a; lanes 6–7: transgenic mouse (4 weeks) maintained on Dox (duplicate); lanes 8–9: transgenic mouse (4 weeks) removed from Dox at birth (duplicate). The 859-bp fragment and the 648-bp fragment represent the tTA RNA and the MMP-13* RNA, respectively. Each reaction was run using c-fos primers as an internal control, spliced mRNA yielding 187 bp, and unspliced mRNA 303 bp. Note, no bands were detected in corresponding lanes containing RNA for PCR that was not treated with M-MLV RT (data not shown). Moreover, PCR fragments were transferred to a nylon membrane and hybridized to a tTA or MMP-13 transgene-specific probe to verify the identity of the PCR product (data not shown).