Chondrocyte hypertrophy is essential for endochondral bone development. Unexpectedly, we discovered that MEF2C, a transcription factor that regulates muscle and cardiovascular development, controls bone development by activating the gene program for chondrocyte hypertrophy. Genetic deletion of Mef2c or expression of a dominant-negative MEF2C mutant in endochondral cartilage impairs hypertrophy, cartilage angiogenesis, ossification, and longitudinal bone growth in mice. Conversely, a superactivating form of MEF2C causes precocious chondrocyte hypertrophy, ossification of growth plates, and dwarfism. Endochondral bone formation is exquisitely sensitive to the balance between MEF2C and the corepressor histone deacetylase 4 (HDAC4), such that bone deficiency of Mef2c mutant mice can be rescued by an Hdac4 mutation, and ectopic ossification in Hdac4 null mice can be diminished by a heterozygous Mef2c mutation. These findings reveal unexpected commonalities in the mechanisms governing muscle, cardiovascular, and bone development with respect to their regulation by MEF2 and class II HDACs.

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Serum response factor (SRF) controls the transcription of muscle genes by recruiting a variety of partner proteins, including members of the myocardin family of transcriptional coactivators. Mice lacking SRF fail to form mesoderm and die before gastrulation, precluding an analysis of the roles of SRF in muscle tissues. To investigate the functions of SRF in skeletal muscle development, we conditionally deleted the Srf gene in mice by skeletal musclespecific expression of Cre recombinase. In mice lacking skeletal muscle SRF expression, muscle fibers formed, but failed to undergo hypertrophic growth after birth. Consequently, mutant mice died during the perinatal period from severe skeletal muscle hypoplasia. The myopathic phenotype of these mutant mice resembled that of mice expressing a dominant negative mutant of a myocardin family member in skeletal muscle. These findings reveal an essential role for the partnership of SRF and myocardin-related transcription factors in the control of skeletal muscle growth and maturation in vivo.hypertrophy ͉ myocardin-related transcription factor ͉ myofiber ͉ myopathy

In response to myocardial infarction (MI), the wound healing response of the left ventricle (LV) consists of overlapping inflammatory, proliferative, and maturation phases; and the cardiac fibroblast is a key cell type involved in each phase. It has recently been appreciated that early post-MI, fibroblasts transform to a pro-inflammatory phenotype and secrete cytokines and chemokines as well as matrix metalloproteinases. Later post-MI, fibroblasts are activated to anti-inflammatory and pro-reparative phenotypes and generate anti-inflammatory and pro-angiogenic factors and extracellular matrix components that form the infarct scar. Additional studies are needed to systematically examine how fibroblast activation shifts over the time frame of MI response and how modulation at different activation stages could alter wound healing and LV remodeling in distinct ways. This review will summarize current fibroblast knowledge as a foundation to discuss existing knowledge gaps.