HCO
 3
 −
 /Cl
 −
 anion exchanger SLC4A2 is required for proper osteoclast differentiation and function

Wu, Jing; Glimcher, Laurie H.; Aliprantis, Antonios O.

doi:10.1073/pnas.0808763105

Cited by 59 publications

(90 citation statements)

References 35 publications

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“…This latter protein is a critical mediator of both osteoclast differentiation and function, where Slc4a2 -/-osteoclasts are unable to resorb mineralized tissue and fail to express TRAP activity (Wu et al, 2008). Taken together, these microarray findings suggested that osteoclast activity and/or bone turnover may be increased in the bgn mice.…”

Section: Discussionmentioning

confidence: 82%

“…fmod -/-samples that are related to osteoclast function/differentiation and bone turnover, including CART prepropeptide (Elefteriou et al, 2005), secreted frizzled-related sequence protein 1 (Hausler et al, 2004), arylsulfatase K (Baron et al, 1990), solute carrier family 4, member 1 (Wu et al, 2008), and protein tyrosine phosphatase, receptor type V (Lee et al, 2007). More specifically, CART prepropeptide inhibits bone resorption by modulating RANKL expression (Elefteriou et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…-/-samples included 3 additional genes associated with osteoclast differentiation and/or function [secreted frizzled-related sequence protein 1 (Hausler et al, 2004), arylsulfatase K (Baron et al, 1990), solute carrier family 4, member 1 (Wu et al, 2008)], and 1 gene associated with bone metabolism [protein tyrosine phosphatase, receptor type V (Lee et al, 2007)] (Table, asterisks). Other genes up-regulated included those related to: cytokinesis of chondrocytes [profilin 1 (Bottcher et al, 2009)], beta secretase cleavage [beta-site APP cleaving enzyme 1 …”

Section: Fmodmentioning

confidence: 99%

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Role of Subchondral Bone during Early-stage Experimental TMJ Osteoarthritis

et al. 2011

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Temporomandibular joint osteoarthritis (TMJ OA) is a degenerative disease that affects both cartilage and subchondral bone. We used microarray to identify changes in gene expression levels in the TMJ during early stages of the disease, using an established TMJ OA genetic mouse model deficient in 2 extracellular matrix proteins, biglycan and fibromodulin ( bgn-/0fmod-/-). Differential gene expression analysis was performed with RNA extracted from 3-week-old WT and bgn-/0fmod-/- TMJs with an intact cartilage/subchondral bone interface. In total, 22 genes were differentially expressed in bgn-/0fmod-/- TMJs, including 5 genes involved in osteoclast activity/differentiation. The number of TRAP-positive cells were three-fold higher in bgn-/0fmod-/- TMJs than in WT. Quantitative RT-PCR showed up-regulation of RANKL and OPG, with a 128% increase in RANKL/OPG ratio in bgn-/0fmod-/- TMJs. Histology and immunohistochemistry revealed tissue disorganization and reduced type I collagen in bgn-/0fmod-/- TMJ subchondral bone. Early changes in gene expression and tissue defects in young bgn-/0fmod-/- TMJ subchondral bone are likely attributed to increased osteoclast activity. Analysis of these data shows that biglycan and fibromodulin are critical for TMJ subchondral bone integrity and reveal a potential role for TMJ subchondral bone turnover during the initial early stages of TMJ OA disease in this model.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Fmodmentioning

confidence: 99%

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Role of Subchondral Bone during Early-stage Experimental TMJ Osteoarthritis

et al. 2011

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“…For Von Kossa staining of extracellular matrix mineralization, cells were fixed with 10% neutral formalin buffer and stained with 2.5% silver nitrate (Sigma-Aldrich). Analysis of osteoclast differentiation and TRAP staining was performed as previously described (45). Serum CTX was measured using the Rat Laps EIA Kit (Immunodiagnostiosystems).…”

Section: Methodsmentioning

confidence: 99%

MLK3 regulates bone development downstream of the faciogenital dysplasia protein FGD1 in mice

Zou¹,

Greenblatt²,

Shim³

et al. 2011

J. Clin. Invest.

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Mutations in human FYVE, RhoGEF, and PH domain-containing 1 (FGD1) cause faciogenital dysplasia (FGDY; also known as Aarskog syndrome), an X-linked disorder that affects multiple skeletal structures. FGD1 encodes a guanine nucleotide exchange factor (GEF) that specifically activates the Rho GTPase CDC42. However, the mechanisms by which mutations in FGD1 affect skeletal development are unknown. Here, we describe what we believe to be a novel signaling pathway in osteoblasts initiated by FGD1 that involves the MAP3K mixed-lineage kinase 3 (MLK3). We observed that MLK3 functions downstream of FGD1 to regulate ERK and p38 MAPK, which in turn phosphorylate and activate the master regulator of osteoblast differentiation, Runx2. Mutations in FGD1 found in individuals with FGDY ablated its ability to activate MLK3. Consistent with our description of this pathway and the phenotype of patients with FGD1 mutations, mice with a targeted deletion of Mlk3 displayed multiple skeletal defects, including dental abnormalities, deficient calvarial mineralization, and reduced bone mass. Furthermore, mice with knockin of a mutant Mlk3 allele that is resistant to activation by FGD1/CDC42 displayed similar skeletal defects, demonstrating that activation of MLK3 specifically by FGD1/CDC42 is important for skeletal mineralization. Thus, our results provide a putative biochemical mechanism for the skeletal defects in human FGDY and suggest that modulating MAPK signaling may benefit these patients. IntroductionIn 1970, Aarskog described an X-linked recessive syndrome characterized by an upturned nose, short stature, multiple dental defects, delayed skeletal age, and multiple bone malformations (1, 2). Later work confirmed these observations, naming the disorder faciogenital dysplasia (FGDY) or Aarskog-Scott syndrome and identified the gene mutated as FYVE, RhoGEF, and PH domain-containing 1 (FGD1) (3). FGD1 encodes a member of the guanine nucleotide exchange factor (GEF) family, which catalyses the exchange of GDP for GTP and promotes the activity of Rho family GTPases (3-6). More than 16 distinct FGD1 mutations have been reported to cosegregate with FGDY. These mutations include deletions and premature truncations, implying that a loss of FGD1 function underlies FGDY (6, 7). Despite these insights into the genetic basis of FGDY, it remains unclear how FGD1 affects bone development.Expression analysis demonstrates that FGD1 is highly expressed in osteoblasts, suggesting that FGD1 signaling plays a critical role in osteoblast differentiation and function (8). Microinjection studies show that FGD1 specifically activates CDC42, a member of the Rho (Ras homology) family of GTPase proteins (4, 5). A

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“…Fzd1 is an antagonist of canonical Wnt/beta-catenin signaling (17), and this signaling pathway plays an important role during tooth development (18,19). SLC4a2 is required for osteoclast differentiation and function (20). It is known that SHH and the SHH signaling pathway play an important role during tooth development (21,22).…”

Section: Methodsmentioning

confidence: 99%

Genetic study of gutter-shaped root (GSR) in AKXL RI mouse strains using QTL analysis

2010

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Keywords: AKXL RI mice; Gutter-shaped root; QTL analysis; dental root fusion rate. IntroductionAbnormal root morphogenesis in human mandibular second or third molars occurs frequently. One of these abnormalities is known as gutter-shaped root (GSR), in which the root appears to be fused. It is well known that root canal treatment of teeth with fused roots is challenging and has a worse prognosis than that for a normal root (1). Teeth with GSR are also likely to have a poor prognosis when affected by periodontal disease. The morphological features of GSR have been reported by many investigators (2,3).It has been reported that C57L/J mice have fused roots similar to GSR on their lower second molars, and they are therefore one of the most useful animal models for studying the cause of GSR formation (4). Previous research has suggested that an autosomal-dominant inheritance pattern affects the development of mouse GSR, and that several genes may be involved (5,6). However, the major gene responsible has not yet been specified. Arita et al. recently reported a new method for measuring mouse GSR as a quantitative trait using micro-CT imaging (7). Therefore, quantitative trait locus (QTL) analysis has become feasible for determining the candidate genes responsible for GSR formation. QTL analysis has been used successfully for identifying chromosomal regions that exert quantitative effects due to poly genes, determining traits such as body weight and susceptibility to alcoholism (8,9).Recombinant inbred (RI) strains of mice are useful for the study of complex traits such as body weight (10,11). RI mouse strains are derived from systematic inbreeding of randomly selected pairs of the F2 generation of a cross between two different inbred strains. The AKXL RI strain is an existing strain derived from the mouse AKR/J and C57L/J progenitor strains, both of which have been well characterized, and show differences in a variety of phenotypes, such as cholesterol gallstone formation (12,13). AKR/J mice do not have abnormal tooth roots. Therefore, it is thought that different strains of AKXL RI mice may have a variety of root shapes in the lower second molar. In this study, we focused on identifying the chromosomal regions involved in mouse GSR formation. Here we report genetic analysis of GSR formation in AKXL RI strains using QTL analysis. Materials and Methods Experiment 1 MiceA total of 44 mice obtained from paternal strains (2 males and 2 females for each of C57L/J, AKR/J, BALB/ cAnNCrlCrlj, C57BL/6J, C3H/HeJ, and DBA/2J) and F1

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HCO ₃ ⁻ /Cl ⁻ anion exchanger SLC4A2 is required for proper osteoclast differentiation and function

Cited by 59 publications

References 35 publications

Role of Subchondral Bone during Early-stage Experimental TMJ Osteoarthritis

Role of Subchondral Bone during Early-stage Experimental TMJ Osteoarthritis

MLK3 regulates bone development downstream of the faciogenital dysplasia protein FGD1 in mice

Genetic study of gutter-shaped root (GSR) in AKXL RI mouse strains using QTL analysis

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HCO 3 − /Cl − anion exchanger SLC4A2 is required for proper osteoclast differentiation and function

Cited by 59 publications

References 35 publications

Role of Subchondral Bone during Early-stage Experimental TMJ Osteoarthritis

Role of Subchondral Bone during Early-stage Experimental TMJ Osteoarthritis

MLK3 regulates bone development downstream of the faciogenital dysplasia protein FGD1 in mice

Genetic study of gutter-shaped root (GSR) in AKXL RI mouse strains using QTL analysis

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HCO ₃ ⁻ /Cl ⁻ anion exchanger SLC4A2 is required for proper osteoclast differentiation and function