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A5.3 Elevated levels of BMP2 compensate for loss of TGF-BETA on proteoglycan level in articular cartilage during experimental osteoarthritis
  1. E N Blaney Davidson,
  2. E L Vitters,
  3. A B Blom,
  4. A P van Caam,
  5. M B Bennink,
  6. W B van den Berg,
  7. F A van de Loo,
  8. P M van der Kraan
  1. Dept Rheumatology, Radboud UMC, Nijmegen, Netherlands

Abstract

Purpose We demonstrated earlier that in aging articular cartilage TGF-beta signalling via Smad2/3 is drastically reduced and loss of Smad2/3signalling predisposed cartilage for OA. We showed that TGF-beta inhibition reduced proteoglycan content in articular cartilage. In contrast, during OA we found elevated levels of BMP2 surrounding cartilage lesions. It is unclear what is the effect of this BMP2 presence on articular cartilage. Therefore, we investigated whether elevated BMP-2 could counteract the loss of TGF-beta signalling during OA.

Methods We made a unique inducible transgenic mouse expressing human BMP2 under control of the Col2a1 promoter only when exposed to doxycycline (Col2a1-rtTA-BMP2). Functionality was tested by measuring human BMP2 mRNA on Q-PCR from articular cartilage, spleen and liver 72 hours after exposure to doxycycline food or standard diet. We induced OA in Col2a1-rtTA-BMP2 by destabilization of the medial meniscus (DMM-model) while treating them with doxycycline- versus standard diet. To study the effect of loss of TGF-beta activity during OA, we additionally intra-articularly injected an adenovirus overexpressing TGF-beta inhibitor LAP (Ad-LAP). Four weeks after DMM-induction knee joints were isolated for histology. OA was scored based on cartilage damage (adapted OARSI score, scale 0-30). Proteoglycan content was measured with digital image analysis in Safranin O stained articular cartilage of the medial tibia.

Results Col2a1-rtTA-BMP2 mice with doxycycline food clearly had elevated expression of hBMP2 mRNA in articular cartilage, but not in spleen and liver thereby confirming functionality of the transgenic animals. Doxycycline exposure in Col2a1-rtTA-BMP2 up to 8 weeks did not result in any detectible alterations in healthy articular cartilage. When OA was induced OA score clearly increased (average of all DMM groups 16.9 versus 2.5 in non-DMM groups), but this was not significantly affected by elevated chondrocyte-specific BMP2. TGF-beta inhibition during DMM significantly reduced the proteoglycan content by 18% compared to DMM alone. BMP2 overexpression only did not affect the proteoglycan content during DMM. Nevertheless, the proteoglycan depletion by inhibition of TGF-beta during DMM was significantly and nearly completely counteracted by elevated chondrocyte-specific BMP2.

Conclusions Our data show that in healthy articular cartilage and in OA cartilage in young animals elevated levels of BMP2 did not have any detectible effects on its own. However, when TGF-beta signalling was lost, a phenomenon occurring in aged individuals, this resulted in decreased levels of PG content in articular cartilage during OA. In this setting, elevated levels of BMP2 could compensate this loss of PG. Therefore the elevated levels of BMP2 near OA lesions could be a reparative response of the articular cartilage. Especially with ageing, when TGF-beta signalling is drastically reduced this compensatory mechanism could be of great importance as an attempt to restore damaged articular cartilage.

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