Abstract
During endochondral ossification, chondrocytes embed themselves in a proteoglycan-rich matrix during the proliferation-maturation transition. Accumulating evidence shows that proteoglycans are essential components for chondrocyte proliferation and differentiation. When we conditionally inactivated FAM20B (Family with sequence similarity 20 member-B), which is a newly identified xylose kinase essential for glycosaminoglycan (GAG) formation on the protein core of proteoglycans, from the dental mesenchyme using Osr2-Cre, which is also strongly expressed in joint cartilage, we found chondrosarcoma in the knee joint and remarkable defects of postnatal ossification in the long bones. Mechanistic analysis revealed that the defects were associated with gain of function in multiple signaling pathways in the epiphyseal chondrocytes, such as those derived by WNT, BMP, and PTHrP/IHH molecules, suggesting that the FAM20B-catalyzed proteoglycans are critical mediators for a signaling balance in the regulatory network controlling chondrocyte differentiation and proliferation. In particular, we demonstrated that the WNT inhibitor was able to rescue part of the bone defects in Osr2-Cre;Fam20Bfl/fl mice, indicating that FAM20B-catalyzed proteoglycans regulate postnatal endochondral ossification partially through the mediation of WNT signaling.
Highlights
In vertebrate animals, most bones develop through a process known as “endochondral ossification”, during which the osteoblasts and bone matrices gradually encroach upon the chondrocytes and cartilagionous matrix after the establishment of primary and secondary ossification centers at the middle and each end of the cartilage templates[1]
Plain X-ray of 30-day-old (P30) conditional knockout (cKO) mice revealed a shorter length and a wider metaphysis in the femurs compared with wild type (WT) (Fig. 1A)
The epiphyseal chondrocytes located at the popliteal side of the joint in cKO mice were not transformed into spongy bones, while those at the patella side were changed (Fig. 2)
Summary
Most bones develop through a process known as “endochondral ossification”, during which the osteoblasts and bone matrices gradually encroach upon the chondrocytes and cartilagionous matrix after the establishment of primary and secondary ossification centers at the middle and each end of the cartilage templates[1]. WNT signaling is generally believed to promote chondrocyte hypertrophy and final maturation[4,5], BMPs induce chondrocyte proliferation and maturation[6], while PTHrP and IHH are known to mediate chondrocyte hypertrophy by forming a negative feedback loop[7]. Compared to these relatively well understood morphogens and growth factors that mediate chondrocyte differentiation, the biological function of proteoglycans that constantly interact with these secreted signaling molecules on the chondrocyte surface and in the extracellular matrix remains poorly understood. The Osr2-Cre;Fam20Bflox/flox mice showed chondrosarcoma in the knee joint and remarkable defects of postnatal ossification in the long bones
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