Our data demonstrate significant levels of BMP-2 in the synovial fluid of all knees without dependency of the presence or the size of a cartilage lesion. This generally indicates a role for BMP-2 in joint metabolism. Furthermore, increased concentrations of BMP-2 were measured following the cartilage regenerating operation. This might be explained as a consequence of the surgical manipulation of the cartilage defect boarder and the arthrotomy as it has been shown for bFGF, IGF-I or IL-1β [
3]. But BMP-2 was the only intraarticular cytokine which correlated with the degree of clinical improvement measured by the IKDC Score. Since it has been shown that the clinical outcome correlates with the degree of cartilage regeneration [
24] it may be concluded that BMP-2 plays a significant role in cartilage repair and metabolism. This is in concordance with other studies showing BMP-2 stimulated murine proteoglycan synthesis and BMP-2 induced enhancement of collagen type II expression in chondrocytes seeded in alginate [
25,
26]. Also, in species like rats and humans, BMP-2 was able to stimulate the chondrogenic phenotype on the mRNA level and induced cartilage extracellular matrix proteoglycan production [
27,
28]. Further studies [
29] have added a partial catabolic effect on cartilage ECM indicating a regulative role for BMP-2 in ECM maintenance, especially during inflammatory induced turnover. This was confirmed by a study that demonstrated a decisive role for BMPs in osteophyte formation and synovial thickening during OA [
30], although the presented data do not allow concluding that BMP-2 plays an important role in the onset of OA, because healthy patients also expressed intraarticular BMP-2. Similar to the effects of BMP-2 stimulation of cartilage-specific extracellular proteins as collagens type II and VI, aggrecan, decorin, fibronectin, hyaluronan [
31‐
34] has been shown
in vitro for BMP-7 (OP-1). It induced anabolic responses in normal and OA chondrocytes from both young and old donors and did not cause expression of cartilage hypertrophy markers or changes in their chondrogenic phenotype [
35‐
37]. BMP-7 was synthesised by human articular chondrocytes [
36,
38] of different age and various degrees of degeneration including OA, but the level of gene and protein expression was dramatically reduced with cartilage aging and degenerative destruction [
36,
37]. BMP-7 was mainly localized in the cartilage layer [
38], but was also detected in the synovial knee fluid of patients with OA and rheumatoid arthritis (RA) [
18]. This articular distribution suggests a decisive paracrine effect of BMP-7, correlating with the finding that intraarticular measured levels are lower than the effective concentrations determined
in vitro[
39]. In conformity with our data the mature and active BMP-7 could not be found in human synovial fluid of normal knees in a recently published study [
18]. The degree of degenerative changes seems to influence the intraarticular concentration and possibly induces the conversion of a BMP-7 pro-form into the mature and active protein [
18]. This is supported by the data of Honsawek et al., who described increased BMP-7 levels in knees of patients with progressive OA [
19] The circumstance that in our trial only patients with circumscribed cartilage lesions were included (and patients with advanced OA were excluded) may make clear why synovial concentrations were mainly found below the detection level and, therefore, did not correlate with the clinical score. Since for both examined BMPs pro-forms [
40] have been described, the role and function of these precursor proteins still need to be analysed.
The statistically significant correlation of BMP-2 levels with the clinical outcome was only found using knee specific scores. In contrast, scores reflecting overall live quality (SF 36) or physical activity (Noyes) failed to show this association. This might be explained by the fact that these scores are influenced by much more parameters than knee function. That the aspect knee functionality plays an important role is shown by the difference between the physical and the mental component summary of the SF 36. Inclusion of more patients could possibly lead to a statistical significance regarding live quality or overall physical activity.
The study does not allow drawing any conclusions how BMP-2 is acting; we even may not determine what part of the operation -arthrotomy or cartilage surgery itself-induces the increase of BMP-2 levels. It also remains unclear what molecular mechanisms are behind the observed association. But the spectrum of BMP-2 effects concerning cartilage repair and differentiation is rapidly growing [
42,
43]. We also may speculate that BMP-2 plays a role in nervous tissue regeneration, thereby influencing pain perception. A further interesting aspect is the question, whether BMP-2 concentrations are linked to differences in bone turnover induced by damage of the subchondral bone layer during surgery. This hypothesis would be supported by the better correlations seen in patients undergoing microfracturing compared to ACI patients. After all, the study does not allow explaining the BMP-2 induced reactions. This limitation is caused by the plain observational characteristic of the study. We speculate that the cartilage in the near surrounding of the defect and the synovia may play an important role controlling BMP-2 release and that the assembly of the different receptors influences BMP-driven effects [
44]. Therefore, a histology study was initiated in order to localize BMPs and their receptors in the different regions of interest in the joint. This will give the possibility to include other promising representatives of the BMP-family with cartilage influencing properties as BMP-4 [
45].