Membrane-type MMPs enable extracellular matrix permissiveness and mesenchymal cell proliferation during embryogenesis
Open accessAbstract
Peri-cellular remodeling of mesenchymal extracellular matrices is considered a prerequisite for cell proliferation, motility and development. Here we demonstrate that membrane-type 3 MMP, MT3-MMP, is expressed in mesenchymal tissues of the skeleton and in peri-skeletal soft connective tissue. Consistent with this localization, MT3-MMP-deficient mice display growth inhibition tied to a decreased viability of mesenchymal cells in skeletal tissues. We document that MT3-MMP works as a major collagenolytic enzyme, enabling cartilage and bone cells to cleave high-density fibrillar collagen and modulate their resident matrix to make it permissive for proliferation and migration. Collectively, these data uncover a novel extracellular matrix remodeling mechanism required for proper function of mesenchymal cells. The physiological significance of MT3-MMP is highlighted in mice double deficient for MT1-MMP and MT3-MMP. Double deficiency transcends the combined effects of the individual single deficiencies and leads to severe embryonic defects in palatogenesis and bone formation incompatible with life. These defects are directly tied to loss of indispensable collagenolytic activities required in collagen-rich mesenchymal tissues for extracellular matrix remodeling and cell proliferation during embryogenesis.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
While osteoclasts express both cathepsin K and MMPs, which contribute differently to bone resorption, BLCs do not express cathepsin K but can efficiently remove nonmineralized fibrillary collagen mediated through their highly active MMPs.
“While osteoclasts express both of these enzymes types, which contribute differently to bone resorption,120 BLCs do not express cathepsin K but can efficiently remove nonmineralized fibrillary collagen (present either on the quiescent bone surface or in resorption lacunae after osteoclastic activity)113 mediated through their highly active MMPs.121”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [121]
Cites
New functions for the matrix metalloproteinases in cancer progression
Egeblad, M., & Werb, Z. (2002) · Nature Reviews Cancer · doi:10.1038/nrc745 · Cited by 6,108 · see citing works
Bone Resorption by Osteoclasts
Teitelbaum, S. L. (2000) · Science · doi:10.1126/science.289.5484.1504 · Cited by 3,962 · see citing works
Structure and function of matrix metalloproteinases and TIMPs
Nagase, H., Visse, R., & MURPHY, G. (2006) · Cardiovascular Research · doi:10.1016/j.cardiores.2005.12.002 · Cited by 3,416 · see citing works
A matrix metalloproteinase expressed on the surface of invasive tumour cells
Sato, H., Takino, T., Okada, Y., Cao, J. P., Shinagawa, A., Yamamoto, E., & Seiki, M. (1994) · Nature · doi:10.1038/370061a0 · Cited by 2,534 · see citing works
COLLAGENOLYTIC ACTIVITY IN AMPHIBIAN TISSUES: A TISSUE CULTURE ASSAY
Gross, J., & Lapiere, C. M. (1962) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.48.6.1014 · Cited by 1,314 · see citing works
Holmbeck, K., Bianco, P., Caterina, J., Yamada, S., Kromer, M., Kuznetsov, S. A., Mankani, M., Gehron Robey, P., Poole, A. R., Pidoux, I., et al. (1999) · Cell · doi:10.1016/s0092-8674(00)80064-1 · Cited by 1,298 · see citing works
Self-citationCollagens, modifying enzymes and their mutations in humans, flies and worms
Myllyharju, J. (2003) · Trends in Genetics · doi:10.1016/j.tig.2003.11.004 · Cited by 1,179 · see citing works
Extracellular matrix remodelling: the role of matrix metalloproteinases
Stamenkovic, I. (2003) · The Journal of Pathology · doi:10.1002/path.1400 · Cited by 1,142 · see citing works
Matrix metalloproteinases: a tail of a frog that became a prince
Brinckerhoff, C., & Matrisian, L. M. (2002) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm763 · Cited by 1,098 · see citing works
Pycnodysostosis, a Lysosomal Disease Caused by Cathepsin K Deficiency
Gelb, B. D., Shi, G., Chapman, H. A., & Desnick, R. J. (1996) · Science · doi:10.1126/science.273.5279.1236 · Cited by 1,022 · see citing works
Ohuchi, E., Imai, K., Fujii, Y., Sato, H., Seiki, M., & Okada, Y. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.4.2446 · Cited by 938 · see citing works
Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice
Säftig, P., Hunziker, E. B., Wehmeyer, O., Jones, S. J., BOYDE, A., Rommerskirch, W., Moritz, J. D., Schu, P. V., & FIGURA, K. V. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.23.13453 · Cited by 909 · see citing works
Zhou, Z., Apte, S., Soininen, R., Cao, R., Baaklini, G. Y., Rauser, R. W., Wang, J., Cao, Y., & Tryggvason, K. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.060037197 · Cited by 791 · see citing works
The cell biology of osteoclast function
Väänänen, H. K., Zhao, H., Mulari, M. T. K., & Halleen, J. M. (2000) · Journal of Cell Science · doi:10.1242/jcs.113.3.377 · Cited by 726 · see citing works
Hotary, K. B., Allen, E. D., Brooks, P. C., Datta, N. S., Long, M. W., & Weiss, S. J. (2003) · Cell · doi:10.1016/s0092-8674(03)00513-0 · Cited by 677 · see citing works
Prespecification and plasticity: shifting mechanisms of cell migration
Friedl, P. (2004) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2003.11.001 · Cited by 670 · see citing works
Altered endochondral bone development in matrix metalloproteinase 13-deficient mice
Stickens, D., Behonick, D. J., Ortéga, N., Heyer, B. S., Hartenstein, B., Yu, Y., Fosang, A., Schorpp‐Kistner, M., Angel, P. E., & Werb, Z. (2004) · Development · doi:10.1242/dev.01461 · Cited by 608 · see citing works
Inada, M., Wang, Y., Byrne, M. H., Rahman, M. U., Miyaura, C., López-Otı́n, C., & Krane, S. M. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0407788101 · Cited by 576 · see citing works
Ushiki, T. (2002) · Archivum histologicum japonicum · doi:10.1679/aohc.65.109 · Cited by 521 · see citing works
Takino, T., Sato, H., Shinagawa, A., & Seiki, M. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.39.23013 · Cited by 471 · see citing works
Even‐Ram, S., & Yamada, K. M. (2005) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2005.08.015 · Cited by 466 · see citing works
Matrix remodeling during endochondral ossification
Ortéga, N., Behonick, D. J., & Werb, Z. (2004) · Trends in Cell Biology · doi:10.1016/j.tcb.2003.12.003 · Cited by 463 · see citing works
The collagen superfamily: from the extracellular matrix to the cell membrane
Ricard‐Blum, S., & Ruggiero, F. (2005) · Pathologie Biologie · doi:10.1016/j.patbio.2004.12.024 · Cited by 428 · see citing works
A cancer cell metalloprotease triad regulates the basement membrane transmigration programPreprint
Hotary, K. B., Li, X.-Y., Allen, E. D., Stevens, S. L., & Weiss, S. J. (2006) · Genes & Development · doi:10.1101/gad.1451806 · Cited by 382 · see citing works
Molecular mechanisms of endochondral bone development
Provot, S., & Schipani, E. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.11.068 · Cited by 374 · see citing works
Itoh, T., Ikeda, T., Gomi, H., Nakao, S., Suzuki, T., & Itohara, S. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.36.22389 · Cited by 356 · see citing works
Chun, T., Sabeh, F., Ota, I., Murphy, H. S., McDonagh, K. T., Holmbeck, K., Birkedal‐Hansen, H., Allen, E. D., & Weiss, S. J. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200405001 · Cited by 348 · see citing works
Self-citationSpecific degradation of the collagen molecule by tadpole collagenolytic enzyme.
Gross, J., & Nagai, Y. (1965) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.54.4.1197 · Cited by 340 · see citing works
Phagocytosis and intracellular digestion of collagen, its role in turnover and remodelling
Everts, V., van der Zee, E., Creemers, L., & Beertsen, W. (1996) · The Histochemical Journal · doi:10.1007/bf02409011 · Cited by 309 · see citing works
Mosig, R., Dowling, O., DiFeo, A. V., Ramirez, M. C. M., Parker, I. C., Abe, E., Diouri, J., Aqeel, A. A., Wylie, J. D., Oblander, S. A., et al. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm060 · Cited by 240 · see citing works
Organization and cellular biology of the perichondrial ossification groove of ranvier
Shapiro, F., Holtrop, M. E., & Glimcher, M. (1977) · Journal of Bone and Joint Surgery · doi:10.2106/00004623-197759060-00001 · Cited by 203 · see citing works
Engelholm, L. H., List, K., Netzel–Arnett, S., Cukierman, E., Mitola, D. J., Aaronson, H., Kjøller, L., Larsen, J. K., Yamada, K. M., Strickland, D. K., et al. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200211091 · Cited by 183 · see citing works
Self-citationRegional regulation of palatal growth and patterning along the anterior–posterior axis in mice
Hilliard, S. A., Yu, L., Gu, S., Zhang, Z., & Chen, Y. P. (2005) · Journal of Anatomy · doi:10.1111/j.1469-7580.2005.00474.x · Cited by 150 · see citing works
MT1-MMP–dependent, apoptotic remodeling of unmineralized cartilage
Holmbeck, K., Bianco, P., Chrysovergis, K., Yamada, S. S., & Birkedal‐Hansen, H. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200307061 · Cited by 134 · see citing works
Self-citationMode of growth, fate and functions of cartilage canals.
Lutfi, A. M. (1970) · PubMed · Cited by 122 · see citing works
Goto, T. (2003) · Journal of Electron Microscopy · doi:10.1093/jmicro/52.6.551 · Cited by 113 · see citing works
Characterization of a truncated recombinant form of human membrane type 3 matrix metalloproteinase
Shimada, T., Nakamura, H., Ohuchi, E., Fujii, Y., Murakami, Y., Sato, H., Seiki, M., & Okada, Y. (1999) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.1999.00459.x · Cited by 103 · see citing works
Highsmith, W. E., Burch, L. H., Zhou, Z., Olsen, J. C., Strong, T. V., Smith, T., Friedman, K. J., Silverman, L. M., Boucher, R. C., Collins, F. S., et al. (1997) · Human Mutation · doi:10.1002/(sici)1098-1004(1997)9:4 · Cited by 89 · see citing works
Blumer, M. J. F., Longato, S., Richter, E., et al. (2005) · Journal of Anatomy · doi:10.1111/j.1469-7580.2005.00404.x · Cited by 81 · see citing works
Kadono, Y., Shibahara, K., Namiki, M., Watanabe, Y., Seiki, M., & Sato, H. (1998) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1998.9531 · Cited by 80 · see citing works
Plaisier, M., Kapiteijn, K., Koolwijk, P., Fijten, C., Hanemaaijer, R., Grimbergen, J. M., Mulder-Stapel, A. A., Quax, P. H. A., Helmerhorst, F. M., & van Hinsbergh, V. W. M. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-0860 · Cited by 74 · see citing works
Matrix Metalloproteinase Dependent and Independent Collagen Degradation
Song, F. (2006) · Frontiers in bioscience · doi:10.2741/2036 · Cited by 67 · see citing works
Kang, T., Yi, J., Yang, W., et al. (2000) · The FASEB Journal · doi:10.1096/fj.00-0269com · Cited by 52 · see citing works
Szabova, L., Yamada, S. S., Birkedal‐Hansen, H., & Holmbeck, K. (2005) · Journal of Cellular Physiology · doi:10.1002/jcp.20385 · Cited by 48 · see citing works
Self-citationMorris-Wiman, J. A., & Brinkley, L. (1992) · The Anatomical Record · doi:10.1002/ar.1092340413 · Cited by 36 · see citing works
Álvarez, J., Costales, L., Lopez-Muniz, A., et al. (2005) · Cell and Tissue Research · doi:10.1007/s00441-004-1034-z · Cited by 28 · see citing works
Palatal closure in the mouse as demonstrated in frozen sections
Greene, R. M., & Kochhar, D. M. (1973) · American Journal of Anatomy · doi:10.1002/aja.1001370409 · Cited by 21 · see citing works
Havemose‐Poulsen, A., Holmstrup, P., Stoltze, K., et al. (1998) · Journal of Periodontal Research · doi:10.1111/j.1600-0765.1998.tb02201.x · Cited by 20 · see citing works
Osteoclast differentiation at growth plate cartilage-trabecular bone junction in newborn rat femur
Sawae, Y. (2003) · Journal of Electron Microscopy · doi:10.1093/jmicro/52.6.493 · Cited by 18 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Bone remodeling: an operational process ensuring survival and bone mechanical competence
Bolamperti, S., Villa, I., & Rubinacci, A. (2022) · Bone Research · doi:10.1038/s41413-022-00219-8 · Cited by 482 · see citing works
MMP-10 Regulates Collagenolytic Activity of Alternatively Activated Resident Macrophages
Rohani, M. G., McMahan, R. S., Razumova, M. V., Hertz, A. L., Cieslewicz, M., Pun, S. H., Regnier, M., Wang, Y., Birkland, T. P., & Parks, W. C. (2015) · Journal of Investigative Dermatology · doi:10.1038/jid.2015.167 · Cited by 101 · see citing works
Molecular pathways of cell-mediated degradation of fibrillar collagen
Sprangers, S., & Everts, V. (2019) · Matrix Biology · doi:10.1016/j.matbio.2017.11.008 · Cited by 102 · see citing works
- Authors
- Shi, J., Son, M.-Y., Yamada, S., Szabova, L., Kahan, S., Chrysovergis, K., Wolf, L., Surmak, A., & Holmbeck, K.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Holmbeck, Kenn
- Venue
- Developmental Biology
- Publisher
- Elsevier BV
- Published
- 2008-01
- Volume
- 313
- Issue
- 1
- Pages
- 196-209
- ISSN
- 0012-1606 (ISSN-L)
- PMC
- PMC2262846
- OpenAlex
- W2012083187
- Cited by
- 107
- References
- 49
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 1 · 2023: 1 · 2022: 5 · 2021: 5 · 2020: 8 · 2019: 5 · 2018: 4 · 2017: 11 · 2016: 7 · 2015: 5 · 2014: 8 · 2013: 4 · 2012: 7
- FWCI
- 2.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Developmental Biology (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (Z99 DE999999)
- National Institute of Dental and Craniofacial Research (Z01DE000676)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Rheumatology › Bone and Dental Protein Studies
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Alkaline Phosphatase Research Studies
- Keywords
- MT3-MMP, MT1-MMP, extracellular matrix remodeling, collagen degradation, fibrillar collagen, mesenchymal cell proliferation, cell migration, embryonic development, palatogenesis, bone formation, cartilage
- MeSH terms
- Metallothionein 3, Animals, Collagen, Extracellular Matrix, Mesoderm, Osteogenesis, Palate, Skull, Mice, Knockout, Cell Proliferation, Mice, Matrix Metalloproteinase 14, Matrix Metalloproteinase 16
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review