Limb overgrowth is a rare pathological condition that may affect either all tissues equally or some tissues selectively and may be associated with other systemic conditions, such as tumorigenesis. While much progress has been made in recent years regarding the molecular mechanisms involved in limb development and, in particular, the formation of new bone, the precise cause of limb overgrowth remains largely unknown. Recent emerging evidence in the converging fields of nerve-tumor biology and limb regeneration has provided evidence that the vascular and peripheral nervous systems might be critically involved in regulating limb size. In this paper, we review the evidence supporting the notion that peripheral nerve abnormalities might cause limb and/or digit overgrowth.
The Molecular Basis of Bone Formation
During embryonic development, mesenchymal progenitor cells form a cartilaginous template that subsequently undergoes ossification to form new bone1,2. Several signaling molecules involved in normal growth plate chondrocyte differentiation have recently been identified3. Growth factors (including growth hormone, insulin-like growth factors, transforming growth factor-beta, and parathyroid hormone-related protein) and fibroblast growth-factor receptors play an important role in this process4,5. Similarly, multiple morphogens, such as bone morphogenetic proteins6, the Wnt-beta-catenin pathway7, and Sonic and Indian hedgehog cascades8, are now known to be critical for proper bone formation.
Growth factor and morphogen signaling converge in the modulation of gene transcription, where Runx2 has been uncovered as a master transcription factor involved in all stages of bone formation and is essential for the initial commitment of mesenchymal cells to the osteoblastic lineage and in regulating the proliferation, differentiation, and maintenance of these cells9. Genetic studies have demonstrated that limb growth and distal limb patterning critically depend on homeobox transcription factors (Hox genes10) and the zinc finger domain transcription factor Gli311 …
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