Details

Autor(en) / Beteiligte

• Gauci, S.J.
• Golub, S.B.
• Tatarczuch, L.
• Lee, E.
• Chan, D.
• Walsh, N.C.
• Little, C.B.
• Stanton, H.
• Lokmic, Z.
• Sims, N.A.
• Mackie, E.J.
• Fosang, A.J.

Titel

Disrupted type II collagenolysis impairs angiogenesis, delays endochondral ossification and initiates aberrant ossification in mouse limbs

Ist Teil von

• Matrix biology, 2019-10, Vol.83, p.77-96

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2019

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Cartilage remodelling and chondrocyte differentiation are tightly linked to angiogenesis during bone development and endochondral ossification. To investigate whether collagenase-mediated cleavage of the major cartilage collagen (collagen II) plays a role in this process, we generated a knockin mouse in which the mandatory collagenase cleavage site at PQG775↓776LAG, was mutated to PPG775↓776MPG (Col2a1Bailey). This approach blocked collagen II cleavage, and the production of putative collagen II matrikines derived from this site, without modifying matrix metalloproteinase expression or activity. We report here that this mouse (Bailey) is viable. It has a significantly expanded growth plate and exhibits delayed and abnormal angiogenic invasion into the growth plate. Deeper electron microscopy analyses revealed that, at around five weeks of age, a small number of blood vessel(s) penetrate into the growth plate, leading to its abrupt shrinking and the formation of a bony bridge. Our results from in vitro and ex vivo studies suggest that collagen II matrikines stimulate the normal branching of endothelial cells and promote blood vessel invasion at the chondro-osseous junction. The results further suggest that failed collagenolysis in Bailey leads to expansion of the hypertrophic zone and formation of a unique post-hypertrophic zone populated with chondrocytes that re-enter the cell cycle and proliferate. The biological rescue of this in vivo phenotype features the loss of a substantial portion of the growth plate through aberrant ossification, and narrowing of the remaining portion that leads to limb deformation. Together, these data suggest that collagen II matrikines stimulate angiogenesis in skeletal growth and development, revealing novel strategies for stimulating angiogenesis in other contexts such as fracture healing and surgical applications. •Col2a1Bailey mouse has collagenase cleavage site at G775↓776L mutated to G775↓776M.•Blocking collagen II cleavage causes abnormal angiogenesis in mouse growth plates.•Failed collagenolysis in Col2a1Bailey mice causes expansion of the hypertrophic zone.•Results suggest that collagen II matrikines stimulate branching of endothelial cells.•Biological rescue of the phenotype features growth plate loss and deformed limbs.