Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose: In murine osteoarthritis (OA) models chondrocytes surrounding lesions express elevated levels of Bone Morphogenetic Protein-2 (BMP2). This growth factor is well known for its ECM inducing qualities and capability to induce new cartilage and bone. The functional consequence of these elevated BMP2 levels near OA lesions is unclear. We made a collagen type II dependent, doxycycline-inducible BMP2 transgenic mouse to investigate the consequence of elevated chondrocyte-specific BMP2 on experimental OA (DMM-model).
Methods: We cloned a lentivirus with BMP2 controlled by minCMV promoter coupled to a tet responsive element (Lv-TRE-BMP2).We crossed a Col2-cre with a floxed rtTA mouse and transfected homozygote embryo’s with Lv-TRE-BMP2 to gain a mouse expressing collagen type 2 dependent BMP2 solely in chondrocytes only upon doxycycline (dox) exposure (Col2-rtTA-TRE-BMP2). Experimental OA was induced (DMM model) in Col2-rtTA-TRE-BMP2 mice with or without dox exposure in food starting one week before DMM, lasting until the end of the experiment (8 weeks after DMM). We isolated knee joints for histology. Left knee joints served as non-OA controls.
Results: Mice with DMM alone showed osteophyte formation predominantly on the medial side of the joint originating from the periost near the femoral-tibial joint and extruding from the medial meniscus. Upon chondrocyte-specific BMP2 exposure, DMM-induced osteophyte formation aggravated severely resulting in outsized osteophytes, enthesophytes on the enthesis of the medial collateral ligament, new bone formation within the collateral ligament near the extruded meniscus and osteophyte formation originating from the femoral growth plate, predominantly but not exclusively on the medial side of the joint. There were no significant differences in non-OA knee joints comparing dox versus non-dox treated transgenics. In contrast, dox treatment resulted in large osteophytes in thoracic or cervical area of the spine. Strikingly, despite apparent changes in knee joint morphology due to large osteophytes there was no detectible difference, with regard to structural damage and Safranin O staining intensity, in cartilage damage when comparing DMM with or without dox exposure.
Conclusion: Elevated BMP2 levels in chondrocytes did not induce structural changes in articular cartilage of young mice. Moreover, unchallenged dox treated joints had no structural alterations in cartilage. In DMM, BMP2 overexpression greatly enhanced de novo cartilage formation, eventually turning into bone (osteophytes), which was not seen in non-OA knee joints with BMP2. We postulate that newly-induced chondrocytes produce high BMP2 levels in dox-treated transgenics, that boost outgrowth of these structures. In spine however, osteophytes developed in dox-treated transgenics without additional triggers. This could rely on chondrocyte precursor subpopulation that is stimulated to undergo chondrogenesis under control of BMP2 alone.
Our data show that chondrocyte-specific elevation of BMP2 levels does not alter the course of cartilage damage in an OA model in young mice but results in severe aggravation of osteophyte formation.
Disclosure:
E. N. Blaney Davidson,
None;
E. L. Vitters,
None;
M. B. Bennink,
None;
F. A. Loo,
None;
W. B. van den Berg,
None;
P. M. van der Kraan,
None.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/chondrocyte-specific-bone-morphogenetic-protein-2-overexpression-results-in-severe-aggravation-of-osteophyte-formation-in-experimental-osteoarthritis-without-altering-cartilage-damage-in-young-mice/