Catabolic mediators from TLR2-mediated proteoglycan aggrecan peptide-stimulated chondrocytes are reduced by Lactobacillus-conditioned media.

In osteoarthritis (OA), extracellular matrix (ECM) digestion by cartilage-degrading enzymes drives cartilage destruction and generates ECM fragments, such as proteoglycan aggrecan (PG) peptides. PG peptides have been shown to induce immunological functions of chondrocytes. However, the role of PG peptides in stimulating catabolic mediators from chondrocytes has not been investigated.

Differential Gene Expression Involved in Bone Turnover of Mice Expressing Constitutively Active TGFβ Receptor Type I.

Transforming growth factor beta (TGF-β) is ubiquitously found in bone and plays a key role in bone turnover. Mice expressing constitutively active TGF-β receptor type I ( mice) are osteopenic. Here, we identified the candidate genes involved in bone turnover in mice using RNA sequencing analysis.

Lipopolysaccharide Impedes Bone Repair in -Deficient Mice.

Chronic inflammation contributes to the development of skeletal disorders in patients with systemic lupus erythematosus (SLE). Activation of the host immune response stimulates osteoclast activity, which in turn leads to bone loss. Regenerating bone in the inflammatory microenvironments of SLE patients with critical bone defects remains a great challenge.

Accelerated Bone Loss in Transgenic Mice Expressing Constitutively Active TGF-β Receptor Type I.

Transforming growth factor beta (TGF-β) is a key factor mediating the intercellular crosstalk between the hematopoietic stem cells and their microenvironment. Here, we investigated the skeletal phenotype of transgenic mice expressing constitutively active TGF-β receptor type I under the control of Mx1-Cre ( mice). μCT analysis showed decreased cortical thickness, and cancellous bone volume in both femurs and mandibles.

High phosphate intake induces bone loss in nephrectomized thalassemic mice.

Although patients with either β-thalassemia or chronic kidney disease (CKD) clinically correlate with severe osteoporosis, the mechanism by which CKD exposed to high phosphate affects bone turnover has not been characterized in β-thalassemia. We aimed to determine the effects of renal insufficiency on high phosphate intake induced changes in bone metabolism after 5/6th nephrectomy in hemizygous β-globin knockout (BKO) mice. Male BKO mice manifested severe anemia and osteopenia.

Identification of candidate regulators of mandibular bone loss in FcγRIIB Mice.

Patients with systemic lupus erythematosus (SLE) have increased inflammatory cytokines, leading to periodontitis and alveolar bone loss. However, the mechanisms driving this phenomenon are still unknown. Here, we have identified novel therapeutic targets for and mediators of lupus-mediated bone loss using RNA-sequencing (RNA-seq) in a FcγRIIB mouse model of lupus associated osteopenia.

Etanercept prevents TNF-α mediated mandibular bone loss in FcγRIIb-/- lupus model.

Patients with systemic lupus erythematosus are at increased risk for alveolar bone loss due to periodontitis possibly as a result of a pathogenic immune response to oral bacteria and inflammation. The aim of the present study was to investigate whether an anti-TNF-α antagonist could prevent mandibular bone loss in the FcγRIIb-/- mouse model of lupus. Mice lacking FcγRIIb had decreased cancellous and cortical bone volume at 6 months of age.

Nephrectomy Does not Exacerbate Cancellous Bone loss in Thalassemic Mice.

Patients with β-thalassemia have an increased risk of developing chronic kidney disease which is associated with osteoporosis and periodontitis. The purpose of this study was to evaluate mandibular and femoral bone change in heterozygous β-globin knockout (BKO) mice following 5/6 nephrectomy (Nx). Female and male BKO mouse blood smears demonstrated microcytic hypochromic anemia.

Mechanical sensing protein PIEZO1 regulates bone homeostasis via osteoblast-osteoclast crosstalk.

Wolff's law and the Utah Paradigm of skeletal physiology state that bone architecture adapts to mechanical loads. These models predict the existence of a mechanostat that links strain induced by mechanical forces to skeletal remodeling. However, how the mechanostat influences bone remodeling remains elusive.

Lupus-like Disease in FcγRIIB Mice Induces Osteopenia.

Osteoporotic fracture is a major cause of morbidity in patients with systemic lupus erythematosus (SLE). Mice lacking Fc gamma receptor IIb (FcγRIIB) spontaneously develop lupus-like disease or SLE at 6-month-old. The aim of this study was to investigate whether FcγRIIB deletion induces osteopenia.

Cathepsin K-deficient osteocytes prevent lactation-induced bone loss and parathyroid hormone suppression.

Lactation induces bone loss to provide sufficient calcium in the milk, a process that involves osteoclastic bone resorption but also osteocytes and perilacunar resorption. The exact mechanisms by which osteocytes contribute to bone loss remain elusive. Osteocytes express genes required in osteoclasts for bone resorption, including cathepsin K (Ctsk), and lactation elevates their expression.

Loss of Gsα in osteocytes leads to osteopenia due to sclerostin induced suppression of osteoblast activity.

The stimulatory subunit of G-protein, Gsα, acts as a secondary messenger of G-protein coupled receptors (GPCRs) that primarily activates cAMP-induced signaling. GPCRs, such as the parathyroid hormone receptor (PTHR), are critical regulators of bone formation as shown by number of genetic manipulation studies targeting early osteoblast lineage cells. In this study, we have examined the role of Gsα in osteocytes, the terminally differentiated and most abundant cells of the osteoblast lineage.

Cortical Bone Loss in a Spontaneous Murine Model of Systemic Lupus Erythematosus.

Patients with systemic lupus erythematosus (SLE), a chronic inflammatory disease characterized by loss of T- and B-cell tolerance to autoantigens, are at increased risk for osteoporosis and fractures. Mice deficient in Fc gamma receptor IIb (FcγRIIB) exhibit spontaneous SLE and its restoration rescues the disease. To determine whether deleting FcγRIIB affects cortical bone mass and mechanical properties, we analyzed cortical bone phenotype of FcγRIIB knockouts at different ages.

Kit Mutation Prevents Cancellous Bone Loss during Calcium Deprivation.

Calcium is essential for normal bone growth and development. Inadequate calcium intake increases the risk of osteoporosis and fractures. Kit ligand/c-Kit signaling plays an important role in regulating bone homeostasis.

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

Coordination between osteoblasts and osteoclasts is required for bone health and homeostasis. Here we show that mice deficient in SMURF2 have severe osteoporosis in vivo. This low bone mass phenotype is accompanied by a pronounced increase in osteoclast numbers, although Smurf2-deficient osteoclasts have no intrinsic alterations in activity.

Disruption of c-Kit Signaling in Kit(W-sh/W-sh) Growing Mice Increases Bone Turnover.

c-Kit tyrosine kinase receptor has been identified as a regulator of bone homeostasis. The c-Kit loss-of-function mutations in WBB6F1/J-Kit(W/W-v) mice result in low bone mass. However, these mice are sterile and it is unclear whether the observed skeletal phenotype is secondary to a sex hormone deficiency.

MEKK2 mediates an alternative β-catenin pathway that promotes bone formation.

Proper tuning of β-catenin activity in osteoblasts is required for bone homeostasis, because both increased and decreased β-catenin activity have pathologic consequences. In the classical pathway for β-catenin activation, stimulation with WNT ligands suppresses constitutive phosphorylation of β-catenin by glycogen synthase kinase 3β, preventing β-catenin ubiquitination and proteasomal degradation. Here, we have found that mitogen-activated protein kinase kinase kinase 2 (MAP3K2 or MEKK2) mediates an alternative pathway for β-catenin activation in osteoblasts that is distinct from the canonical WNT pathway.

CHMP5 controls bone turnover rates by dampening NF-κB activity in osteoclasts.

Physiological bone remodeling requires that bone formation by osteoblasts be tightly coupled to bone resorption by osteoclasts. However, relatively little is understood about how this coupling is regulated. Here, we demonstrate that modulation of NF-κB signaling in osteoclasts via a novel activity of charged multivesicular body protein 5 (CHMP5) is a key determinant of systemic rates of bone turnover.

Specific bone cells produce DLL4 to generate thymus-seeding progenitors from bone marrow.

Production of the cells that ultimately populate the thymus to generate α/β T cells has been controversial, and their molecular drivers remain undefined. Here, we report that specific deletion of bone-producing osteocalcin (Ocn)-expressing cells in vivo markedly reduces T-competent progenitors and thymus-homing receptor expression among bone marrow hematopoietic cells. Decreased intrathymic T cell precursors and decreased generation of mature T cells occurred despite normal thymic function.

Loss of BMPR2 leads to high bone mass due to increased osteoblast activity.

Imbalances in the ratio of bone morphogenetic protein (BMP) versus activin and TGFβ signaling are increasingly associated with human diseases yet the mechanisms mediating this relationship remain unclear. The type 2 receptors ACVR2A and ACVR2B bind BMPs and activins but the type 2 receptor BMPR2 only binds BMPs, suggesting that type 2 receptor utilization might play a role in mediating the interaction of these pathways. We tested this hypothesis in the mouse skeleton, where bone mass is reciprocally regulated by BMP signaling and activin and TGFβ signaling.

Stk11 (Lkb1) deletion in the osteoblast lineage leads to high bone turnover, increased trabecular bone density and cortical porosity.

The mTOR pathway couples energy homeostasis to growth, division and survival of the cell. Stk11/Lkb1 is a critical serine-threonine protein kinase in the inhibition of mTOR pathway action. In the mammalian skeleton, Stk11 regulates the transition between immature and hypertrophic chondrocytes.

Inhibiting stromal cell heparan sulfate synthesis improves stem cell mobilization and enables engraftment without cytotoxic conditioning.

The glycosyltransferase gene, Ext1, is essential for heparan sulfate production. Induced deletion of Ext1 selectively in Mx1-expressing bone marrow (BM) stromal cells, a known population of skeletal stem/progenitor cells, in adult mice resulted in marked changes in hematopoietic stem and progenitor cell (HSPC) localization. HSPC egressed from BM to spleen after Ext1 deletion.

FGF-21 and skeletal remodeling during and after lactation in C57BL/6J mice.

Lactation is associated with significant alterations in both body composition and bone mass. Systemic and local skeletal factors such as receptor activator of nuclear factor κ-B ligand (RANKL), PTHrP, calcitonin, and estrogen are known to regulate bone remodeling during and after lactation. Fibroblast growth factor 21 (FGF-21) may function as an endocrine factor to regulate body composition changes during lactation by inducing gluconeogenesis and fatty acid oxidation.

Protein tyrosine phosphatases ε and α perform nonredundant roles in osteoclasts.

Female mice lacking protein tyrosine phosphatase ε (PTP ε) are mildly osteopetrotic. Osteoclasts from these mice resorb bone matrix poorly, and the structure, stability, and cellular organization of their podosomal adhesion structures are abnormal. Here we compare the role of PTP ε with that of the closely related PTP α in osteoclasts.

Deficiency of retinaldehyde dehydrogenase 1 induces BMP2 and increases bone mass in vivo.

The effects of retinoids, the structural derivatives of vitamin A (retinol), on post-natal peak bone density acquisition and skeletal remodeling are complex and compartment specific. Emerging data indicates that retinoids, such as all trans retinoic acid (ATRA) and its precursor all trans retinaldehyde (Rald), exhibit distinct and divergent transcriptional effects in metabolism. Despite these observations, the role of enzymes that control retinoid metabolism in bone remains undefined.