K-7174 protects against OA pathogenesis through blockade of the
Background and Purpose Osteoarthritis (OA) is a leading cause
of disability and bears a large socioeconomic cost, but we lack an
effective disease-modifying therapy. There is great need to identify
novel target molecules in OA pathogenesis. Here, by asking why old
cartilage appears to be more sensitive to OA pathogenic factors, we
identified the importance and underlying mechanism of K-7174 as a
blocker of the Zmiz1-GATA axis in age-related OA pathogenesis.
Experimental Approach As a novel transcriptional regulator in
OA pathogenesis, Zmiz1 was isolated as an up-regulated gene from aged
cartilage, using microarray and Ingenuity Pathway Analysis (IPA).
Infection and intra-articular injection of Ad-Zmiz1 were performed in
vitro and in vivo. Cartilage-specific Col2a1-Zmiz1 TG mice with or
without DMM (destabilization of the medial meniscus) surgery were
evaluated by measurement of OA manifestations. To identify a specific
Zmiz1-related transcription factor and a potential inhibitor, we
performed transcription factor, in silico binding, and inhibition
assays. Key Results The transcriptional regulator, Zmiz1, is
up-regulated in old mouse cartilage and highly expressed in damaged
cartilage of OA patients and DMM mice. Col2a1-Zmiz1 TG mice and
DMM-induced Col2a1-Zmiz1 TG mice showed more severe cartilage
destruction. Overexpression of Zmiz1 induced cartilage destruction by
up-regulating Mmps and Cox2 through activation of the Zmiz1-GATA axis.
Finally, we demonstrate that K-7174 interfered with the activation of
the Zmiz1-GATA axis to crucially protect against OA pathogenesis and
promote ECM synthesis. Conclusion and Implications The
K-7174-mediated blockade of the Zmiz1-GATA axis could be a useful
therapeutic strategy for blocking OA pathogenesis.