Chondrocyte-Derived Bone Cells Determine the Overall Pattern of TMJ Condyle and Contribute to Bone Remodeling
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abstract
TMD (Temporomandibular joint disorders) affect 5-10% of the population in this country, with severe TMDrequiring surgical repair. The cause for TMD is often hard to determine, and the pathophysiology underlying thisaffliction remains unclear, as the mandibular condylar cartilage (MCC) differs considerably in its developmentand structure from both a growth plate or an articular cartilage. However, the regulation of TMJ development andgrowth has been under-studied. Chondrogenesis in the TMJ or limbs has been considered a linked but separateprocess from osteogenesis during endochondral bone formation. How can the inherited message be transmittedfrom chondrocytes, which supposedly undergo cell death before bone formation, to the cells that form bone?The answer to this question may lie in recent studies indicating that a direct transformation of chondrocytes toosteoblasts occurs. Yet, the following key questions remain: how is this cell transformation linked to bone growthand remodeling? What is the underlying molecular mechanism? Which genes are required for celltransformation? We propose that chondrogenesis and osteogenesis are one continuous process in whichchondrocyte-derived bone cells (CBC) define the overall pattern of MCC-ramus and contribute to boneremodeling via Bmpr1a (BMP receptor 1a, a key receptor for BMP2 and BMP4) and ï¢-catenin. This hypothesisis based on: 1) Published data from our lab and others demonstrating that direct cell transformation occurs inMCC and limbs; 2) Deleting Bmpr1a or ï¢-catenin in chondrocytes leads to drastic changes in the condyle andlimbs during growth and bone remodeling, though deletion of either gene in bone cells has little impact on theskeletal pattern; and 3) The molecular regulation of cell transformation is highly dependent on the skeletalelements, developmental stage, and different genes. We will test this hypothesis using the following highlyrelated but independent Aims: 1) To determine molecular regulation of cell transformation by Bmpr1a duringgrowth and bone remodeling. Working hypothesis: the CBC defines the overall morphology of the condyle andlimbs via BMPR1A that plays variant roles in different elements of the skeleton; and 2): To determine molecularregulation of cell transformation by ï¢-catenin during growth and bone remodeling. Working hypothesis: ï¢-cateninplays variant roles in the condyle vs. limbs in defining skeletal pattern and bone remodeling in a manner thatdiffers from Bmpr1a; and 3): To determine how chondrocytes demineralize cartilage matrices and form bonecells ex vivo, and shift expression profiles of genes directly linked to bone cells in vitro. Working hypothesis:HCs, which migrate, play a dual role in removing calcified cartilage and cell transformation. We expect that CBCis responsible for most endochondral bone formation and remodeling, regulated by Bmpr1a and ï¢-catenin. Wepredict that this phenomenon also occurs in limbs, although differentially regulated by these genes. Finishingthis project will likely revise the current dogma, provide new knowledge in this understudied area, and form abasis for developing novel approaches to prevent, diagnose, and treat TMD, as well as other skeletal diseases.
