Osteophytes, ie, bony outgrowths that limit joint movement and cause pain, are a hallmark of (secondary) osteoarthritis (OA), but how their formation is regulated is still unclear. Bone morphogenetic protein 2 (BMP2) has been implicated as an important mediator of osteophyte formation. When we investigated the ability of BMP2 to induce osteophytes, we noticed that especially in OA conditions BMP2 can induce large osteophytes. In this study we tried to elucidate which OA-related factor(s) enable(s) this BMP2 effect.Materials and methods
Col2-rtTA-TRE-BMP2 mice were used, which express BMP2 when exposed to doxycycline in cells having expressed collagen type II. Doxycycline was administered via the food from 7 days before onset of each experiment and onwards. To study if an inflammatory mediator enables BMP2-induced osteophyte formation, either IL1β or zymosan was injected intra-articularly, and saline injections were used as control. To investigate if transforming growth factor β (TGFβ) signalling enables BMP2-induced osteophytes, TGFβ1 was either overexpressed in low dose using an adenovirus, or inhibited during experimental OA as induced by destabilisation of the medial meniscus (DMM) by adenoviral overexpression of its inhibitor: latency associated peptide (LAP).Results
In these mice, doxycycline-induced BMP2 expression in cartilage did not result in spontaneous osteophyte formation. Inflammation, induced by either a simple trigger like IL1β or a more complex trigger like zymosan did not trigger BMP2-mediated osteophyte formation, but BMP2 did enhance zymosan induced synovial thickening and cartilage damage. In experimental OA, BMP2 enhanced osteophyte formation, but strikingly inhibition of TGFβ did normalise BMP2 mediated osteophyte formation to control level. Furthermore, overexpression of TGFβ in a dose that predominantly resulted in fibrosis, resulted in severe osteophyte formation in the presence of BMP2.Conclusions
Our data show that BMP2 induced osteophyte formation is greatly enhanced by an additional trigger. Inflammatory factors released during OA are unlikely to be such an osteophyte-formation activation trigger. More likely TGFβ activity is the key factor that facilitates BMP2 mediated osteophyte formation.