The fibulins are a family of secreted glycoproteins associated with basement membranes, elastic fibers, and other matrices. They are expressed in a variety of tissues. Association with these matrix structures is mediated by their ability to interact with many extracellular matrix constituents. The seven members of the family are defined by the presence of two structural modules, a tandem repeat of epidermal growth factor-like modules and a unique C-terminal fibulin-type module. They act not only as intermolecular bridges within the extracellular matrix to form supramolecular structures, but also as mediators for cellular processes and tissue remodeling. These important functions of fibulins in a wide range of biological processes have been shown in in vitro systems, gene knockout mice, and human genetic disorders. In this review, we describe the structure and function of these proteins and discuss the implication of fibulins in development and diseases.

Cartilage plays an important role in mechanical load resistance and in skeletal structure support. It also serves as the skeletal template for endochondral ossification by which most bones in the body, such as long bones, are formed. In endochondral ossification, cartilage development is initiated by mesenchymal cell condensation, followed by a series of proliferation and differentiation processes. Cells undergoing condensation differentiate into chondrocytes, which then proliferate, produce type II collagen and form the proliferative zone of the cartilage molds. As development proceeds, chondrocytes in the center of the cartilage molds (prehypertrophic zone) cease proliferating and differentiate into type X collagen-producing hypertrophic chondrocytes to form the hypertrophic zone. Terminally differentiated hypertrophic chondrocytes mineralize the surrounding matrix. Eventually these cells die by apoptosis and are replaced by osteoblasts that form trabecular bone.The regulation of chondrocyte proliferation and differentiation must be tightly coordinated to allow formation of properly sized cartilage and bone (1). Parathyroid hormone-related peptide (PTHrP) 2 and parathyroid hormone (PTH) sustain chondrocyte proliferation and delay differentiation of the growth plate (2). PTHrP is expressed by perichondrial cells and chondrocytes in the upper region of growing cartilage. Mutant mice that are deficient in PTHrP (3), PTH (4), or its receptor (5) have short proliferative zones and accelerated chondrocyte differentiation, which results in abnormal endochondral bone formation. In contrast, mice that overexpress PTHrP have enlarged proliferative zones and delayed chondrocyte terminal differentiation (6). Humans with an activating mutation in the PTH/ PTHrP receptor develop Jansen metaphyseal chondrodysplasia, characterized by disorganization of the growth plates and delayed chondrocyte terminal differentiation (7). These results suggest that PTH/PTHrP signaling regulates skeletal development by promoting cell proliferation and inhibiting hypertrophic differentiation of chondrocytes.The binding of PTH/PTHrP to its receptor activates both G s and G q family heterotrimeric G proteins (8, 9). The activation of G s is necessary for cAMP production and protein kinase A (PKA) activation, which leads to phosphorylation of the cAMPresponse element-binding (CREB) family of transcription factors. CREB then induces genes such as the cyclin D1 and cyclin A genes. The activated cyclin/cyclin-dependent kinases in turn phosphorylate the retinoblastoma protein and its relative factors, which then dissociates the E2F transcription factor and subsequently activates the target genes necessary for DNA replication and cell cycle progression. Thus, CREB is a direct target of PKA and a downstream target of PTH/PTHrP/cAMP signaling and is required for chondrocyte proliferation (10, 11). How proliferation signaling is down-regulated in the prehypertrophic zone to stop proliferation and allow the switch to the postmitotic state is not well unde...

In tooth morphogenesis, the dental epithelium and mesenchyme interact reciprocally for growth and differentiation to form the proper number and shapes of teeth. We previously identified epiprofin (Epfn), a gene preferentially expressed in dental epithelia, differentiated ameloblasts, and certain ectodermal organs. To identify the role of Epfn in tooth development, we created Epfn-deficient mice (Epfn ؊/؊ ). Epfn ؊/؊ mice developed an excess number of teeth, enamel deficiency, defects in cusp and root formation, and abnormal dentin structure. Mutant tooth germs formed multiple dental epithelial buds into the mesenchyme. In Epfn ؊/؊ molars, rapid proliferation and differentiation of the inner dental epithelium were inhibited, and the dental epithelium retained the progenitor phenotype. Formation of the enamel knot, a signaling center for cusps, whose cells differentiate from the dental epithelium, was also inhibited. However, multiple premature nonproliferating enamel knot-like structures were formed ectopically. These dental epithelial abnormalities were accompanied by dysregulation of Lef-1, which is required for the normal transition from the bud to cap stage. Transfection of an Epfn vector promoted dental epithelial cell differentiation into ameloblasts and activated promoter activity of the enamel matrix ameloblastin gene. Our results suggest that in Epfn-deficient teeth, ectopic nonproliferating regions likely bud off from the self-renewable dental epithelium, form multiple branches, and eventually develop into supernumerary teeth. Thus, Epfn has multiple functions for cell fate determination of the dental epithelium by regulating both proliferation and differentiation, preventing continuous tooth budding and generation.