SMURF2 regulates bone homeostasis by disrupting SMAD3 interaction with vitamin D receptor in osteoblasts

Subject Code:H06 With the support by the National Natural Science Foundation of China,a study by the research group led by Prof.Zou Weiguo(邹卫国)from the Institute of Biochemistry and Cell Biology,Shanghai Institutes for Biological Sciences,CAS demonstrates that E3ligase SMURF2maintains bone

The Role of T Lymphocytes in Bone Remodeling

Bone remodeling is a tightly regulated resorption and formation of bone matrix for physiological processes or to maintain bone function. Bone remodeling involves the synchronized differentiation and activity of bone-related cell types including bone matrix-depositing osteoblasts, bone matrix-resorbing osteoclasts, collagen/extracellular matrix-producing chondrocytes, and the progenitors of these cell types. T and B cells are adaptive immune cells that can influence bone remodeling by directly regulating the function of bone-related cells under normal and pathophysiological conditions. The specific mechanisms through which T cells control remodeling are not well defined. Here, we review the impact and influence of T cells and their products on the differentiation and function of bone cells during bone remodeling. Synthesizing new connections and highlighting potential mechanisms may promote additional avenues of study to elucidate the full role that immune cells play in regulating bone homeostasis.

TGF-β and BMP signaling in osteoblast,skeletal development,and bone formation,homeostasis and disease

INTRODUCTIONThe transforming growth factor-β （TGF-β） superfamily com- prises TGF-βs, Activin, bone morphogenetic proteins （BMPs） and other related proteins. TGF-β superfamily members act through a heteromeric receptor complex,, comprised of type I and type II receptors at the cell surface that transduce intracellular signals via Smad complex or mitogen-activated protein kinase （MAPK） cascade.

Research Progress in Function and Regulation of E3 Ubiquitin Ligase SMURF1

Smad ubiquitylation regulatory factor 1(Smurf1)is an important homologous member of E6-AP C-terminus type E3 ubiquitin ligase.Initially,Smurf1 was reportedly involved in the negative regulation of the bone morphogenesis protein(BMP)pathway.After further research,several studies have confirmed that Smurf1 is widely involved in various biological processes,such as bone homeostasis regulation,cell migration,apoptosis,and planar cell polarity.At the same time,recent studies have provided a deeper understanding of the regulatory mechanisms of Smurf1’s expression,activity,and substrate selectivity.In our review,a brief summary of recent important biological functions and regulatory mechanisms of E3 ubiquitin ligase Smurf1 is proposed.

Wnt signaling:Essential roles in osteoblast differentiation,bone metabolism and therapeutic implications for bone and skeletal disorders

Wnt signaling executes an indispensable performance in osteoblast differentiation,bone development,homeostasis,and remodeling.Wnt signals trigger the intracellular Wnt signaling cascade to initiate regulating the implication of b-catenin in the bone environment.Going through the novel discoveries done via high-throughput sequencing technologies on ge-netic mouse models,we highlighted the significant contribution of Wnt ligands,co-receptors,inhibitors,their related skeletal phenotypes in mouse models and the similar bone disorders clinically observed in human beings.Moreover,the crosstalk between Wnt signaling pathway and BMP,TGF-b,FGF,Hippo,Hedgehog,Notch and PDGF signaling pathways is thoroughly demonstrated to be the underlying gene regulatory network that orchestrates osteoblast dif-ferentiation and bone development.We also introspected the significance of Wnt signaling transduction in the reorganization of cellular metabolism by stimulating glycolysis,glutamine catabolism,and fatty acid oxidation in osteoblast-lineage cells that display an important reg-ulatory arbor in the cellular bioenergetics of the bone.Throughout this evaluation,most to date therapeutical approaches towards osteoporosis and other bone maladies found in human beings,are formulated with an aspiration to holistically revamp the present clinical applica-tions involving various monoclonal antibodies therapies that lack specificity,efficacy,and safety into more requisite advanced therapeutics that satisfy these three requirements for further clinical considerations.Conclusively,our review provides comprehensive scientific findings related to the fundamental significance of Wnt signaling cascades in skeletal system and the underlying gene regulatory network with other signaling pathways enlightening re-searchers with the possibility to further integrate the identified target molecules into thera-peutic strategies for skeletal disorders treatment in the clinic.

Targeting Kindlin-2 in adipocytes increases bone mass through inhibiting FAS/PPARγ/FABP4 signaling in mice

Osteoporosis(OP)is a systemic skeletal disease that primarily affects the elderly population,which greatly increases the risk of fractures.Here we report that Kindlin-2 expression in adipose tissue increases during aging and high-fat diet fed and is accompanied by decreased bone mass.Kindlin-2 specific deletion(K2KO)controlled by Adipoq-Cre mice or adipose tissue-targeting AAV(AAV-Rec2-CasRx-sgK2)significantly increases bone mass.Mechanistically,Kindlin-2 promotes peroxisome proliferator-activated receptor gamma(PPARγ)activation and downstream fatty acid binding protein 4(FABP4)expression through stabilizing fatty acid synthase(FAS),and increased FABP4 inhibits insulin expression and decreases bone mass.Kindlin-2 inhibition results in accelerated FAS degradation,decreased PPARγactivation and FABP4 expression,and therefore increased insulin expression and bone mass.Interestingly,we find that FABP4 is increased while insulin is decreased in serum of OP patients.Increased FABP4 expression through PPARγactivation by rosiglitazone reverses the high bone mass phenotype of K2KO mice.Inhibition of FAS by C75 phenocopies the high bone mass phenotype of K2KO mice.Collectively,our study establishes a novel Kindlin-2/FAS/PPARγ/FABP4/insulin axis in adipose tissue modulating bone mass and strongly indicates that FAS and Kindlin-2 are new potential targets and C75 or AAV-Rec2-CasRx-sgK2 treatment are potential strategies for OP treatment.

Essence of"Shen(Kidney)Controlling Bones":Conceptual Analysis Based on Hypothalamic-Pituitary-Adrenal-Osteo-Related Cells Axis

As a traditional concept of Chinese medicine（CM）, the theory of ＂Shen（Kidney） controlling bones＂ has been gradually proven. And in modern allopathic medicine, the multiple mechanisms of bone growth, development and regeneration align with the theory. Shen deficiency as a pathological condition has a negative effect on the skeleton of body, specifically the disorder of bone homeostasis. Present studies indicate that Shen deficiency shares a common disorder characterized by dysfunction of hypothalamic-pituitary-adrenal（HPA） axis. HPA axis may be an important regulator of bone diseases with abnormal homeostasis. Therefore, we posit the existence of hypothalamic-pituitary-adrenal-osteo-related cells axis： cells that comprise bone tissue（osteo-related cells） are targets under the regulation of HPA axis in disorder of bone homeostasis. Chinese herbs for nourishing Shen have potential in the development of treatments for disorder of bone homeostasis.

New Insights into the Molecular Basis of Kidney Governing Bone Theory

Kidney governing bone theory plays an important role in treating bone metabolic disease such as osteoporosis, and many tonifying kidney prescriptions/herbs are widely used in Traditional Chinese Medicine(TCM). However, the exact biological basis of kidney governing bone theory in the context of new advances in biology is still not fully established. In this paper, the content of kidney governing bone theory in biology has been fully demonstrated from different aspects. We first propose that bone and kidney mutually affect each other in pathology and physiology, particularly through homeostasis of calcium, phosphorus and fibroblast growth factor-23(FGF-23). Next, we identify that tonifying kidney prescriptions/herbs exert bone protective effects, thus treating osteoporosis by regulating bone formation and bone resorption.Furthermore, the exact molecular mechanisms of tonifying kidney prescriptions, herbs and their effective components in treating osteoporosis have been systematically reviewed. Finally, we come into the conclusion that kidney regulating bone mineral homeostasis, bone protective effects of tonifying kidney herbs and regulatory effects on bone homeostasis are all the manifestations of kidney governing bone theory.Therefore, the new insights into kidney governing bone theory in biology will promote the development of clinical practices, and drugs discovery in treating osteoporosis.

From Osteoblast to Osteoclast: New Insights of Yin-Yang Theory in Bone Remodeling

Yin-Yang theory plays critical role in traditional Chinese medicine(TCM) science. However, there are many competing interpretations of YinYang theory in the context with the development in biology, and no consensus has been established. Here we first propose that osteoblast should be regarded as Yin, while osteoclast should be considered as Yang in bone remodeling compartment(BRC). Our conceptions are consistent with the following key findings: 1)osteoblast and osteoclast both derive from the embryonic ectoderm; 2)osteoblast and osteoclast work collaboratively in BRC to maintain bone homeostasis; 3)the activities of osteoblast and osteoclast are coupled to remain dynamic balance;4)osteoblast and osteoclast exert their function in ceaseless successions. Moreover, we argue that Yin-Yang relationships exist between osteoblast and osteoclast: osteoblast secretes the receptor activator for nuclear factor-κB ligand(RANKL) and the monocyte/macrophage colony-stimulating factor(M-CSF) and osteoprotegerin(OPG) to positively or negatively regulate osteoclast differentiation and function.Meanwile, osteoclast and bone resorption in turn release cytokines, such as transforming growth factor-β(TGF-β), insulin-like growth factor-1(IGF-1) from bone matrix, to regulate osteoblast differentiation and function. Next, the unlimited division of Yin-Yang can be applied to divide sublevel of Yin-Yang inside osteoblast or osteoclast. Finally, Yin-Yang relationship of osteoblast and osteoclast is relative. Therefore, we come into the conclusion that the relationships between osteoblast and osteoclast as established in contemporary biology reflect the classic Yin-Yang in bone remodeling. The new Yin-Yang concepts of osteoblast and osteoclast may strengthen basic theory and clinical practice in TCM.

The role of lipid metabolism in osteoporosis:Clinical implication and cellular mechanism

In recent years,researchers have become focused on the relationship between lipids and bone metabolism balance.Moreover,many diseases related to lipid metabolism dis-orders,such as nonalcoholic fatty liver disease,atherosclerosis,obesity,and menopause,are associated with osteoporotic phenotypes.It has been clinically observed in humans that these lipid metabolism disorders promote changes in osteoporosis-related indicators bone mineral density and bone mass.Furthermore,similar osteoporotic phenotype changes were observed in high-fat and high-cholesterol-induced animal models.Abnormal lipid metabolism(such as increased oxidized lipids and elevated plasma cholesterol)affects bone microenvironment ho-meostasis via cross-organ communication,promoting differentiation of mesenchymal stem cells to adipocytes,and inhibiting commitment towards osteoblasts.Moreover,disturbances in lipid metabolism affect the bone metabolism balance by promoting the secretion of cyto-kines such as receptor activator of nuclear factor-kappa B ligand by osteoblasts and stimulating the differentiation of osteoclasts.Conclusively,this review addresses the possible link be-tween lipid metabolism disorders and osteoporosis and elucidates the potential modulatory mechanisms and signaling pathways by which lipid metabolism affects bone metabolism bal-ance.We also summarize the possible approaches and prospects of intervening lipid meta-bolismforosteoporosistreatment.