hang Z

Foxp1/2/4 regulate endochondral ossification as a suppresser complex

Osteoblast induction and differentiation in developing long bones is dynamically controlled by the opposing action of transcriptional activators and repressors. In contrast to the long list of activators that have been discovered over past decades, the network of repressors is not well-defined. Here we identify the expression of Foxp1/2/4 proteins, comprised of Forkhead-box (Fox) transcription factors of the Foxp subfamily, in both perichondrial skeletal progenitors and proliferating chondrocytes during endochondral ossification. Mice carrying loss-of-function and gain-of-function Foxp mutations had gross defects in appendicular skeleton formation. At the cellular level, over-expression of Foxp1/2/4 in chondroctyes abrogated osteoblast formation and chondrocyte hypertrophy. Conversely, single or compound deficiency of Foxp1/2/4 in skeletal progenitors or chondrocytes resulted in premature osteoblast differentiation in the perichondrium, coupled with impaired proliferation, survival, and hypertrophy of chondrocytes in the growth plate. Foxp1/2/4 and Runx2 proteins interacted in vitro and in vivo, and Foxp1/2/4 repressed Runx2 transactivation function in heterologous cells. This study establishes Foxp1/2/4 proteins as coordinators of osteogenesis and chondrocyte hypertrophy in developing long bones and suggests that a novel transcriptional repressor network involving Foxp1/2/4 may regulate Runx2 during endochondral ossification.

FOXP1 controls mesenchymal stem cell commitment and senescence during skeletal aging

A hallmark of aged mesenchymal stem/progenitor cells (MSCs) in bone marrow is the pivot of differentiation potency from osteoblast to adipocyte coupled with a decrease in self-renewal capacity. However, how these cellular events are orchestrated in the aging progress is not fully understood. In this study, we have used molecular and genetic approaches to investigate the role of forkhead box P1 (FOXP1) in transcriptional control of MSC senescence. In bone marrow MSCs, FOXP1 expression levels declined with age in an inverse manner with those of the senescence marker p16INK4A. Conditional depletion of Foxp1 in bone marrow MSCs led to premature aging characteristics, including increased bone marrow adiposity, decreased bone mass, and impaired MSC self-renewal capacity in mice. At the molecular level, FOXP1 regulated cell-fate choice of MSCs through interactions with the CEBP&bgr;/&dgr; complex and recombination signal binding protein for immunoglobulin &kgr; J region (RBPj&kgr;), key modulators of adipogenesis and osteogenesis, respectively. Loss of p16INK4A in Foxp1-deficient MSCs partially rescued the defects in replication capacity and bone mass accrual. Promoter occupancy analyses revealed that FOXP1 directly represses transcription of p16INK4A. These results indicate that FOXP1 attenuates MSC senescence by orchestrating their cell-fate switch while maintaining their replicative capacity in a dose- and age-dependent manner.

Comparison of dental education and professional development between mainland China and North America.

Different educational and professional developments within the dental field create different sets of missions, norms, and practices regarding dental diseases and their appropriate treatment. This review has addressed differences in dental education and professional development between mainland China and North America. Many factors influence the choice of model and it is very difficult to predict which model will become predominant. However, there is growing sentiment that the independent faculty model in North America is logical and superior to the model, which integrates dental and medical education in mainland China. Many North America dental schools place a high priority on preclinical and clinical training in the curriculum in order to expose students to patient oral health needs and systemic dental problems much earlier than in mainland China. North America dental schools promote and embrace students self-learning skills by the use of PBL, CRL, and TRAD education methodologies and new e-based technologies and approaches whereby students learn rather than are taught. In mainland China, the traditional lecture-based format is still employed in the majority of dental schools; however, strategies to enhance students self-learning skills is increasingly utilised in most well-known Chinese dental schools. The Chinese dental education model, which treats dentistry as a sub-specialty of medicine, has brought about fundamental differences, with the dentist functioning essentially as a stomatologist. For example, China has built up a large oral and maxillofacial surgery society, and craniofacial surgery is performed to a much broader extent by Chinese dentists than by most North American counterparts. In North America, dentists engage in full-time work, attend continuing training/education programmes, belong to an association, gain legal status, and construct a code of ethics emphasising the quality of care delivered to the public. Currently, continuing dental education in North America is available through a variety of venues involving licensing authorities, universities and private programmes. The concept of professional development in mainland China is relatively new and is still considered primarily in the context of promotion or achieving a higher professional title. Mandatory continuing dental professional education requirements do not guarantee the competence of members of the profession. Today, the Chinese government and society place increasing emphasis upon the accountability of self-regulating professions. Rather than attempting to summarise the current scope of dental education and professional development between mainland China and North America, this paper hopes to enhance mutual understanding, and promote greater academic exchanges in dental education.

p38α MAPK Regulates Lineage Commitment and OPG Synthesis of Bone Marrow Stromal Cells to Prevent Bone Loss under Physiological and Pathological Conditions.

Summary Bone marrow-derived mesenchymal stromal cells (BM-MSCs) are capable of differentiating into osteoblasts, chondrocytes, and adipocytes. Skewed differentiation of BM-MSCs contributes to the pathogenesis of osteoporosis. Yet how BM-MSC lineage commitment is regulated remains unclear. We show that ablation of p38α in Prx1+ BM-MSCs produced osteoporotic phenotypes, growth plate defects, and increased bone marrow fat, secondary to biased BM-MSC differentiation from osteoblast/chondrocyte to adipocyte and increased osteoclastogenesis and bone resorption. p38α regulates BM-MSC osteogenic commitment through TAK1-NF-κB signaling and osteoclastogenesis through osteoprotegerin (OPG) production by BM-MSCs. Estrogen activates p38α to maintain OPG expression in BM-MSCs to preserve the bone. Ablation of p38α in BM-MSCs positive for Dermo1, a later BM-MSC marker, only affected osteogenic differentiation. Thus, p38α mitogen-activated protein kinase (MAPK) in Prx1+ BM-MSCs acts to preserve the bone by promoting osteogenic lineage commitment and sustaining OPG production. This study thus unravels previously unidentified roles for p38α MAPK in skeletal development and bone remodeling.

Bone Size and Quality Regulation: Concerted Actions of mTOR in Mesenchymal Stromal Cells and Osteoclasts

Summary The bone size and quality, acquired during adolescent growth under the influence of anabolic hormones, growth factors, and nutrients, determine the height and bone stability and forecast osteoporosis risks in late life. Yet bone size and quality control mechanisms remain enigmatic. To study the roles of mammalian target of rapamycin (mTOR) signaling, sensor of growth factors and nutrients, in bone size and quality regulation, we ablated Tsc1, a suppressor of mTOR, in mesenchymal stromal cells (MSCs), monocytes, or their progenies osteoblasts and osteoclasts. mTOR activation in MSCs, but much less in osteoblasts, increased bone width and mass due to MSC hyperproliferation, but decreased bone length and mineral contents due to defective MSC differentiation. mTOR activation promotes bone mineral accretion by inhibiting osteoclast differentiation and activity directly or via coupling with MSCs. Tuberous sclerosis complex patient studies confirmed these findings. Thus, mTOR regulates bone size via MSCs and bone quality by suppressing catabolic activities of osteoclasts.

p38α MAPK regulates proliferation and differentiation of osteoclast progenitors and bone remodeling in an aging-dependent manner

Bone mass is determined by the balance between bone formation, carried out by mesenchymal stem cell-derived osteoblasts, and bone resorption, carried out by monocyte-derived osteoclasts. Here we investigated the potential roles of p38 MAPKs, which are activated by growth factors and cytokines including RANKL and BMPs, in osteoclastogenesis and bone resorption by ablating p38α MAPK in LysM+monocytes. p38α deficiency promoted monocyte proliferation but regulated monocyte osteoclastic differentiation in a cell-density dependent manner, with proliferating p38α−/− cultures showing increased differentiation. While young mutant mice showed minor increase in bone mass, 6-month-old mutant mice developed osteoporosis, associated with an increase in osteoclastogenesis and bone resorption and an increase in the pool of monocytes. Moreover, monocyte-specific p38α ablation resulted in a decrease in bone formation and the number of bone marrow mesenchymal stem/stromal cells, likely due to decreased expression of PDGF-AA and BMP2. The expression of PDGF-AA and BMP2 was positively regulated by the p38 MAPK-Creb axis in osteoclasts, with the promoters of PDGF-AA and BMP2 having Creb binding sites. These findings uncovered the molecular mechanisms by which p38α MAPK regulates osteoclastogenesis and coordinates osteoclastogenesis and osteoblastogenesis.

Foxp2 regulates anatomical features that may be relevant for vocal behaviors and bipedal locomotion

Significance Speech and bipedalism are key aspects of behavior that emerged during human evolution. FOXP2, a gene implicated in a human speech and language disorder, has been suggested to contribute to language evolution. Here, through knockout studies of mouse Foxp2, we show that this gene is not only important for neural circuits involved in vocal behaviors, it also helps regulate relevant anatomical substrates. We additionally demonstrate that Foxp2 influences skeletal features that may be relevant for bipedal locomotion. Our findings raise the possibility that FOXP2 might be important for anatomical features contributing to derived human traits, including speech and bipedalism. Fundamental human traits, such as language and bipedalism, are associated with a range of anatomical adaptations in craniofacial shaping and skeletal remodeling. However, it is unclear how such morphological features arose during hominin evolution. FOXP2 is a brain-expressed transcription factor implicated in a rare disorder involving speech apraxia and language impairments. Analysis of its evolutionary history suggests that this gene may have contributed to the emergence of proficient spoken language. In the present study, through analyses of skeleton-specific knockout mice, we identified roles of Foxp2 in skull shaping and bone remodeling. Selective ablation of Foxp2 in cartilage disrupted pup vocalizations in a similar way to that of global Foxp2 mutants, which may be due to pleiotropic effects on craniofacial morphogenesis. Our findings also indicate that Foxp2 helps to regulate strength and length of hind limbs and maintenance of joint cartilage and intervertebral discs, which are all anatomical features that are susceptible to adaptations for bipedal locomotion. In light of the known roles of Foxp2 in brain circuits that are important for motor skills and spoken language, we suggest that this gene may have been well placed to contribute to coevolution of neural and anatomical adaptations related to speech and bipedal locomotion.