Alternative splicing of type II procollagen: IIB or not IIB?

Abstract

Over two decades ago, two isoforms of the type II procollagen gene (COL2A1) were discovered. These isoforms, named IIA and IIB, are generated in a developmentally-regulated manner by alternative splicing of exon 2. Chondroprogenitor cells synthesize predominantly IIA isoforms (containing exon 2) while differentiated chondrocytes produce mainly IIB transcripts (devoid of exon 2). Importantly, this IIA-to-IIB alternative splicing switch occurs only during chondrogenesis. More recently, two other isoforms have been reported (IIC and IID) that also involve splicing of exon 2; these findings highlight the complexities involving regulation of COL2A1 expression. The biological significance of why different isoforms of COL2A1 exist within the context of skeletal development and maintenance is still not completely understood. This review will provide current knowledge on COL2A1 isoform expression during chondrocyte differentiation and what is known about some of the mechanisms that control exon 2 alternative splicing. Utilization of mouse models to address the biological significance of Col2a1 alternative splicing in vivo will also be discussed. From the knowledge acquired to date, some new questions and concepts are now being proposed on the importance of Col2a1 alternative splicing in regulating extracellular matrix assembly and how this may subsequently affect cartilage and endochondral bone quality and function.

• Alternative splicing
• cartilage
• chondrocyte differentiation
• extracellular matrix
• precursor mRNA
• type II procollagen
• type XI collagen

Acknowledgements

Thank you to Dr. Thomas Hering (T.H.) for assistance in calculating splice site strength scores (Figure 2). Thanks also to Soumya Ravindran and Louisa Wirthlin for generating the immunofluorescence data shown in Figure 4. Research involving the Col2a1^+ex2 mice received funding from an NIH R21 grant (AR053513; to A.M.) and a Pilot & Feasibility grant provided from an NIH Musculoskeletal P30 Core Grant (P30 AR057235; to A.M.). Research on Col2a1-mIIC mice was funded by an NIH R21 grant (RR025397; to A.M and T.H).