Is collagenase (matrix metalloproteinase-1) necessary for bone and other connective tissue remodeling?
In physiologic remodeling of bone and other connective tissues, proteinases such as the matrix metalloproteinases (MMPs) which can cleave Type I collagen play a critical role. In bone, MMP-1 is secreted by stromal fibroblasts, osteoblasts, and osteoclasts. Only the collagenases (MMP-1 and MMP-8) cleave native undenatured collagen at neutral pH. The cleavage is site specific at a single locus in the alpha 1(I) chain between Gly775/Ile776. The authors have altered the amino acid sequences around the collagenase cleavage site by site-directed mutagenesis of the murine Col1a-I gene, introducing Pro for Gln774, Pro for Ala777, and Met for Ile776. The mutant Col1a-I gene has been expressed in Mov13 fibroblasts, and secreted Type I collagen molecules have been found to be resistant to cleavage at Gly775/Ile776 by MMP-1 or MMP-8. This subtle mutation was introduced recently into the endogenous Col1a-I gene by homologous recombination in embryonic stem cells to determine the role of collagenase in vivo. Chimaeric mice derived from blastocysts injected with these embryonic stem cells transmitted the mutant Col1a-I gene to their offspring. Surprisingly, homozygous mutant mice reproduce and appear to develop normally. The mechanisms of collagen resorption in remodeling of bone and soft tissues in these mice are being examined currently. Information should be derived that will be useful in interpreting human disorders characterized by increased collagen deposition, such as osteopetrosis and dermal fibrosis.
Krane
S M
SM
Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
D000595:Amino Acid Sequence; D000818:Animals; D016723:Bone Remodeling; D003094:Collagen / Q000235:genetics; D017364:Collagenases / Q000235:genetics / Q000502:physiology*; D003238:Connective Tissue / Q000502:physiology*; D004792:Enzyme Precursors / Q000235:genetics; D006801:Humans; D020781:Matrix Metalloproteinase 1; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D012038:Regeneration
D004792:Enzyme Precursors; D003094:Collagen; D017364:Collagenases; C022440:procollagenase; D020781:Matrix Metalloproteinase 1