Our long-term goal is to understand the molecular mechanisms regulating growth plate development. The last step in maturation of the growth plate is the differentiation of proliferative chondrocytes into hypertrophic chondrocytes, which subsequently undergo endochondral ossification. Our recent findings indicate that histone deacetylation 4 (HDAC4) nuclear-cytoplasmic shuttling, degradation, and translational repression plays a major role in this process. Specifically, we suspect that HDAC4 functions as a negative regulator of chondrocyte hypertrophy by binding and inhibiting Runx 2/Cbfa1 expression in the nucleus. Runx 2/Cbfa1 is a transcription factor necessary for chondrocyte differentiation and hypertrophy. However, the mechanisms underlying HDAC4 shuttling, degradation, and translational repression are as yet undetermined. Our overall hypothesis is that the relocation, degradation, and translational repression of HDAC4 control chondrocyte differentiation and are regulated by Ca2+/calmodulin kinase IV (CaMKIV), p38 MAP kinase, and microRNA-1 respectively at different zone in the growth plate. The hypothesis includes three specific aims:
Specific Aim 1 : To determine whether activation of the Ca2+/calmodulin signaling pathway prevents nuclear entry of HDAC4 and enhances the binding of HDAC4 to the cytoplasmic binding protein 14-3-3. This may impair HDAC4-mediated inhibition of chondrocyte differentiation in the nucleus. Hypothesis 1 is that HDAC4 nuclear- cytoplasmic shuttling controls chondrocyte differentiation and is dependent on the Ca2+/calmodulin signaling pathway.
Specific Aim 2 : To determine whether: 2a) caspases degrade HDAC4;2b) p38 MAPK regulates expression or activity of capsases 2 and 3;2c) Runx2 expression is dependent on p38 MAPK by in situ hybridization in p38 MAPK defective and constitutively activated MKK6 mouse growth plates. Project 2b will be tested using active MKK6 to elevate p38 and dominant negative p38 MAPK to repress p38. Hypothesis 2 is that HDAC4 degradation is regulated by P38 MAPK by increasing expression of caspases 2 and 3.
Specific Aim 3 : To determine whether: 3a) the spatio-temporal distribution of specific miRNA-1 is different during growth plate development;3b) miRNA-1 downregulates HDAC4 by repressing HDAC4 translation at 3'UTR in the chondrocytes;3c) miRNA-1regulates chondrocyte proliferation and differentiation. Hypothesis 3 is that microRNA-1 is involved in chondrocyte hypertrophy regulation by repressing HDAC4 translation. Significance of the growth plate, or physis, determines the future length and shape of the human mature bone. Delineating the physiological controls of the physis could suggest possibilities for therapeutically manipulating endochondral bone growth by modulating the signaling pathways that govern the association of HDAC4 with Runx2. Prevention of leg length discrepancy, dwarfism, and other disorders of bone growth might also be possible once molecular triggers and stops affecting the growth plate are better understood.
Although many factors have been found to impact the function of the growth plate, its biology remains poorly understood. The importance of clearly delineating the physiological controls of the physis by histone deacetylation cannot be overemphasized. Such knowledge could allow the prevention or correction of a number of bone-growth related problems in adults and children. Leg length discrepancy and dwarfism are just a few clinical dilemmas that may be provided with more elegant solutions if the molecular triggers and stops to the growth plate can be elucidated. The understanding of cell differentiation in growth plate may also be important to the understanding of abnormal chondrocyte differentiation in osteoarthritis.
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