Regulatory Mechanisms of Prg4 and Gdf5 Expression in Articular Cartilage and Functions in Osteoarthritis.

Owing to the rapid aging of society, the numbers of patients with joint disease continue to increase. Accordingly, a large number of patients require appropriate treatment for osteoarthritis (OA), the most frequent bone and joint disease. Thought to be caused by the degeneration and destruction of articular cartilage following persistent and excessive mechanical stimulation of the joints, OA can significantly impair patient quality of life with symptoms such as knee pain, lower limb muscle weakness, or difficulty walking. Because articular cartilage has a low self-repair ability and an extremely low proliferative capacity, healing of damaged articular cartilage has not been achieved to date. The current pharmaceutical treatment of OA is limited to the slight alleviation of symptoms (e.g., local injection of hyaluronic acid or non-steroidal anti-inflammatory drugs); hence, the development of effective drugs and regenerative therapies for OA is highly desirable. This review article summarizes findings indicating that proteoglycan 4 (Prg4)/lubricin, which is specifically expressed in the superficial zone of articular cartilage and synovium, functions in a protective manner against OA, and covers the transcriptional regulation of Prg4 in articular chondrocytes. We also focused on growth differentiation factor 5 (Gdf5), which is specifically expressed on the surface layer of articular cartilage, particularly in the developmental stage, describing its regulatory mechanisms and functions in joint formation and OA pathogenesis. Because several genetic studies in humans and mice indicate the involvement of these genes in the maintenance of articular cartilage homeostasis and the presentation of OA, molecular targeting of Prg4 and Gdf5 is expected to provide new insights into the aetiology, pathogenesis, and potential treatment of OA.

Smoc1 and Smoc2 regulate bone formation as downstream molecules of Runx2.

Runx2 is an essential transcription factor for bone formation. Although osteocalcin, osteopontin, and bone sialoprotein are well-known Runx2-regulated bone-specific genes, the skeletal phenotypes of knockout (KO) mice for these genes are marginal compared with those of Runx2 KO mice. These inconsistencies suggest that unknown Runx2-regulated genes play important roles in bone formation. To address this, we attempted to identify the Runx2 targets by performing RNA-sequencing and found Smoc1 and Smoc2 upregulation by Runx2. Smoc1 or Smoc2 knockdown inhibited osteoblastogenesis. Smoc1 KO mice displayed no fibula formation, while Smoc2 KO mice had mild craniofacial phenotypes. Surprisingly, Smoc1 and Smoc2 double KO (DKO) mice manifested no skull, shortened tibiae, and no fibulae. Endochondral bone formation was also impaired at the late stage in the DKO mice. Collectively, these results suggest that Smoc1 and Smoc2 function as novel targets for Runx2, and play important roles in intramembranous and endochondral bone formation.