Trabecular bone formation is the last step in endochondral ossification. This remodeling process of cartilage into bone involves blood vessel invasion and removal of hypertrophic chondrocytes (HTCs) by chondroclasts and osteoclasts. Periosteal- and chondrocyte-derived osteoprogenitors utilize the leftover mineralized HTC matrix as a scaffold for primary spongiosa formation. Here, we show genetically that β-catenin (encoded by Ctnnb1), a key component of the canonical Wnt pathway, orchestrates this remodeling process at multiple levels. Conditional inactivation or stabilization of β-catenin in HTCs by a Col10a1-Cre line locally modulated osteoclastogenesis by altering the Rankl:Opg ratio in HTCs. Lack of β-catenin resulted in a severe decrease of trabecular bone in the embryonic long bones. Gain of β-catenin activity interfered with removal of late HTCs and bone marrow formation, leading to a continuous mineralized hypertrophic core in the embryo and resulting in an osteopetrotic-like phenotype in adult mice. Furthermore, β-catenin activity in late HTCs is required for chondrocyte-derived osteoblastogenesis at the chondro-osseous junction. The latter contributes to the severe trabecular bone phenotype in mutants lacking β-catenin activity in HTCs.
Loss- and gain-of function approaches modulating canonical Wnt/β-catenin activity have established a role for the Wnt/β-catenin pathway during tooth development. Here we show that Wnt/β-catenin signaling is required in the dental mesenchyme for normal incisor development, as locally restricted genetic inactivation of β-catenin results in a splitting of the incisor placode, giving rise to two incisors. Molecularly this is first associated with down-regulation of Bmp4 and subsequent splitting of the Shh domain at a subsequent stage. The latter phenotype can be mimicked by ectopic application of the BMP antagonist Noggin. Conditional genetic inactivation of Bmp4 in the mesenchyme reveals that mesenchymal BMP4 activity is required for maintenance of Shh expression in the dental ectoderm. Taken together our results indicate that β-catenin together with Lef1 and Tcf1 are required to activate Bmp4 expression in order to maintain Shh expression in the dental ectoderm. This provides a mechanism whereby the number of incisors arising from one placode can be varied through local alterations of a mesenchymal signaling circuit involving β-catenin, Lef1, Tcf1 and Bmp4.
Ror1 is a member of the Ror-family receptor tyrosine kinases. Ror1 is broadly expressed in various tissues and organs during mouse embryonic development. However, so far little is known about its function. The closely related family member Ror2 was shown to play a crucial role in skeletogenesis and has been shown to act as a co-receptor for Wnt5a mediating non-canonical Wnt-signaling. Previously, it has been shown that during embryonic development Ror1 acts in part redundantly with Ror2 in the skeletal and cardiovascular systems. In this study, we report that loss of the orphan receptor Ror1 results in a variety of phenotypic defects within the skeletal and urogenital systems and that Ror1 mutant mice display a postnatal growth retardation phenotype. Developmental Dynamics 239:2266-2277,
Bone tissue engineering is a promising approach for treatment of defective and lost bone in the maxillofacial region. Creating functional tissue for load bearing bone reconstruction using biocompatible and biodegradable scaffolds seeded with living cells is of crucial importance. The aim of our study was to compare the effects of poly-lactic-co-glycolic acid (PLGA) and hydroxyapatite (HA) ceramic granulae on growth, differentiation, mineralization and gene expression of mandibular mesenchymal cambial layer precursor cells (MCLPCs) cultured onto tissue engineered three-dimensional (3-D) composites in vitro. These 3-D composites were cultivated in a rotating cultivation system under osteogenic differentiation conditions for a maximum period of 21 days. After 6 and 21 days, histological examination was performed; scanning electron microscopy (SEM), alkaline phosphatase (ALP) activity and levels of DNA were investigated. Expression of bone-specific genes osteocalcin, osteonectin, osteopontin, ALP, core binding factor alpha 1 and collagen type I were investigated by using a reverse transcription-polymerase chain reaction (RT-PCR) method. After 6 and 21 days of incubation an initiation of mineralization and the presence of newly formed bone at the surface of the composites were shown after evaluation of ALP activity, DNA content, SEM and histological staining. Expression of bone-specific genes confirmed the bone-like character of these composites and different effects of PLGA or HA granulae on the osteogenic differentiation of human MCLPCs in vitro. The results of this study support the concept that substrate signals significantly influence MCLPCs growth, differentiation, mineralization and gene expression in vitro, and that the use of these cells in the manufacturing of 3-D cell/HA composites is a promising approach for load bearing bone reconstruction in the maxillofacial region in vivo.
One mechanism by which 1,25(OH)(2)Vitamin D(3) controls cell growth might be the upregulation of p21. As p21 was unsusceptible to 1,25(OH)(2)Vitamin D(3) in SCC25, other inhibiting proteins were necessary to be tested. The proven upregulation of p18 seems to be the responsible step for growth inhibition of 1,25(OH)(2)Vitamin D(3) in SCC25.
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