BMPR1A is necessary for chondrogenesis and osteogenesis while BMPR1B prevents hypertrophic differentiation

Abstract

BMP2 stimulates bone formation and signals preferably through BMP receptor (BMPR) 1A while GDF5 is rather a cartilage inducer and signals preferably through BMPR1B. Consequently, BMPR1A and BMPR1B are believed to be involved in bone and cartilage formation, respectively. However, their function is not yet fully clarified. In this study, GDF5 mutants with a decreased affinity for BMPR1A were generated. These mutants, GDF5 and BMP2 were tested for BMPR1A or BMPR1B dimerization with BMPR2 and for their chondrogenic, hypertrophic and osteogenic properties in chondrocytes, in the multipotent mesenchymal precursor cells C3H10T1/2, and the human osteosarcoma cell line Saos-2. Mutants with the lowest potency for BMPR1A/BMPR2 dimerization exhibited minimal chondrogenic and osteogenic activities indicating that BMPR1A is necessary for chondrogenic and osteogenic differentiation. BMP2, GDF5 and the R399E mutant stimulated expression of chondrogenic and hypertrophy markers in C3H10T1/2 cells and chondrocytes. However, R399E which dimerized BMPR1B and BMPR2 more potently than GDF5 or BMP2, displayed reduced hypertrophic activity. Therefore, we postulate that stronger BMPR1B signaling, compared to BMPR1A signaling, prevent chondrocyte hypertrophy and act as a cartilage stabilizer during joint morphogenesis.