Inducible chondrocyte-specific overexpression of BMP2 in young mice results in severe aggravation of osteophyte formation in experimental OA without altering cartilage damage.
OBJECTIVE
In osteoarthritis (OA) chondrocytes surrounding lesions express elevated bone morphogenetic protein 2 (BMP2) levels. To investigate the functional consequence of chondrocyte-specific BMP2 expression, we made a collagen type II dependent, doxycycline (dox)-inducible BMP2 transgenic mouse and studied the effect of elevated BMP2 expression on healthy joints and joints with experimental OA.


METHODS
We cloned a lentivirus with BMP2 controlled by a tet-responsive element and transfected embryos of mice containing a collagen type II driven cre-recombinase and floxed rtTA to gain a mouse expressing BMP2 solely in chondrocytes and only upon dox exposure (Col2-rtTA-TRE-BMP2). Mice were treated with dox to induce elevated BMP2 expression. In addition, experimental OA was induced (destabilisation of the medial meniscus model) with or without dox supplementation and knee joints were isolated for histology.


RESULTS
Dox treatment resulted in chondrocyte-specific upregulation of BMP2 and severely aggravated formation of osteophytes in experimental OA but not in control mice. Moreover, elevated BMP2 levels did not result in alterations in articular cartilage of young healthy mice, although BMP2-exposure did increase VDIPEN expression in the articular cartilage. Strikingly, despite apparent changes in knee joint morphology due to formation of large osteophytes there were no detectible differences in articular cartilage: none with regard to structural damage nor in Safranin O staining intensity when comparing destabilisation of the medial meniscus with or without dox exposure.


CONCLUSIONS
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.
Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
E N
EN
Blaney Davidson
Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
E L
EL
Vitters
Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
M B
MB
Bennink
Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
P L E M
PL
van Lent
Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
A P M
AP
van Caam
Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
A B
AB
Blom
Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
W B
WB
van den Berg
Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
F A J
FA
van de Loo
Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
P M
PM
van der Kraan
D000818:Animals; D001169:Arthritis, Experimental / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics* / Q000378:metabolism; D002358:Cartilage, Articular / Q000473:pathology*; D019902:Chondrocytes / Q000378:metabolism*; D008592:Menisci, Tibial / Q000601:surgery; D051379:Mice; D008822:Mice, Transgenic; D010003:Osteoarthritis / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D054850:Osteophyte / Q000000981:diagnostic imaging*; D012333:RNA, Messenger / Q000378:metabolism*; D011859:Radiography; D013264:Stifle / Q000000981:diagnostic imaging* / Q000473:pathology; D015854:Up-Regulation
C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D012333:RNA, Messenger