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First published online August 25, 2006
doi: 10.1242/10.1242/dev.02532
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Correspondence |
Institute of Pathology, University of Leipzig, Leipzig, Germany
e-mail: thomas.aigner{at}medizin.uni-leipzig.de
In their study of a novel chordin-like BMP inhibitor, CHL2, Nakayama and
colleagues (Nakayama et al.,
2004
) report on a newly identified BMP inhibitor that is
specifically expressed in developing articular cartilages, as well as in
connective tissues in reproductive organs. They also show the induction of
CHL2 in mesenchymal progenitor cells during chondrogenic differentiation.
After maturation, chondrocytes repress CHL2 expression. This, together with
the functional properties of CHL2, is well shown in this overall very
instructive paper. Interestingly, the authors also try to relate CHL2
expression and function to osteoarthritic cartilage degeneration of the
joints. This is an important attempt to gain insights into the aetiology of
this disorder from findings generated by basic research. Unfortunately, this
aspect of the paper contains, in our opinion, a substantial mistake.
Nakayama and colleagues report on the re-initiation of CHL2 expression in
osteoarthritic chondrocytes, a phenomenon that might obviously interrupt the
potentially important activation of chondrocytes by BMPs: in particular, BMP2
and BMP7 are known to enhance the anabolic activity of adult articular
chondrocytes (Chubinskaya et al.,
2000; Fan et al.,
2004). In fact, knockdown of BMP activity using antisense
technology has recently been suggested to cause a significant imbalance in the
anabolic-catabolic activity of articular chondrocytes in articular cartilage
(Soeder et al., 2005).
Therefore, the misregulation of a BMP-antagonistic molecule such as CHL2 in
osteoarthritic chondrocytes might cause the downregulation of chondrocyte
anabolic activity and, thus, enhance the disease process. However, despite
being an attractive concept, the proposed upregulation of BMP-inhibitory
activity in osteoarthritic cartilage does not agree with some of the published
data: first, many studies have shown that an overall upregulation of anabolic
activity occurs in osteoarthritic chondrocytes
(Aigner et al., 1992;
Lippiello et al., 1977) and not
a downregulation, as would be expected by the expression pattern reported by
the authors. In particular, middle zone chondrocytes are anabolically
hyperactive (Aigner et al.,
1992; Aigner et al.,
1997) and osteoarthritic chondrocytes appear to be rather
hyper-than hyporeactive to BMPs (Fan et
al., 2004).
Osteophytic cartilage is not osteoarthritic degenerated cartilage
It appears from figures 6B and 6C in Nakayama et al.
(Nakayama et al., 2004) that
the authors reported on osteophytic cartilage and not on degenerated
osteoarthritic cartilage. These tissue types are found in many osteoarthritic
joints, but are, however, biologically and developmentally very different
(Aigner et al., 1995).
There are several features that distinguish osteoarthritic from osteophytic
cartilage. Osteophytes are osteo-cartilaginous outgrowths that form mostly at
the margins of osteoarthritic joints. Osteophytes derive from precursor cells
within periosteal or synovial tissue and often merge with or overgrow the
original articular cartilage. Osteophytic cartilage shows, depending on the
stage of development (Gelse et al.,
2003), many different features, and can closely resemble primary
joint cartilage. In general, osteophytic cartilage is hypercellular (Fig. 6B),
lacks a defined tidemark (Fig. 6B,C), and often a defined subchondral bone
plate (Fig. 6C). It shows instead ingrowing vessels (Fig. 6C), and the
extracellular matrix often shows a fibrocartilagenous appearance (Fig. 6B). We
believe that these features identify the tissues shown in Fig. 6B and 6C as
being osteophytic tissue despite their limited resolution. Clearly,
distinguishing these two tissues types from each other is not easy, but
histologists trained in joint morphology and pathology can usually do so.
Osteophytic tissue recapitulates chondroneogenesis in the adult
Osteophyte growth essentially re-capitulates chondroneogenesis in fetal
development (Aigner et al.,
1995; Gelse et al.,
2003): thus, depending on the stage, more or less mature cartilage
formation is observed, as well as processes like endochondral ossification.
Osteophyte tissues derive from mesenchymal precursor cells. After being in a
chondroprogenitor cell state, the cells become active matrix-producing
chondrocytes. Finally, some of them become hypertrophic. In the lowest zones
of osteophytes [well visible in Fig. 6C of Nakayama et al.
(Nakayama et al., 2004)],
vessels grow in and endochondral ossification takes place. Thus, overall
osteophytic chondrocytes resemble, in many respects, fetal chondrocytes. This
possibly explains why Nakayama and colleagues observed CHL2 being strongly
expressed in these newly formed chondrocytes, as in the chondrocytes of the
fetal growth plate investigated in their study. In fact, similar to fetal
chondrogenesis, BMPs and TGFßs are thought to play an important role in
osteophyte formation, and intra-articular application of these molecules has
been shown to initiate osteophyte formation
(Van Beuningen et al.,
1998).
Conclusion
Clearly, CHL2 represents a new BMP-inhibitory molecule, which is a very interesting finding for cartilage and osteoarthritis research. If the expression of CHL2 is confirmed in normal adult chondrocytes, it could confirm CHL2 as an important player in the homeostasis of cartilage matrix maintenance. It will be even more interesting to investigate changes in the expression levels of CHL2 in primary degenerated osteoarthritic chondrocytes in vivo.
Note added in proof
The authors of the original article were invited to respond but did not take up the opportunity to do so.
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