Extracellular matrix protein 1, a direct targeting molecule of parathyroid hormone‐related peptide, negatively regulates chondrogenesis and endochondral ossification<i>via</i>associating with progranulin growth factor

Kong, Li; Zhao, Yunpeng; Tian, Qingyun; Feng, Jianquan; Kobayashi, Tatsuya; Merregaert, J.; Liu, Chuanju

doi:10.1096/fj.201600261r

Cited by 22 publications

(18 citation statements)

References 55 publications

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“…Elevation of ALT could be coupled with the significant weight loss we observed because no other liver enzymes in the females were affected. Lack of additional significant findings in the full blood chemistry panel strengthens the specificity of the targeted ablation of bone cells as others have reported, (10,11,25,29) because no signs of organ damage were detected.…”

Section: Discussionsupporting

confidence: 61%

“…IGF-1, which is higher in males than females during puberty, appears to be the primary determinant of skeletal sexual dimorphism, and likely interacts with both estrogens and androgens to elicit even greater differences in phenotype. (1,2) In the OCN-Cre/Igf1r flox/flox , it was reported that "abnormalities described… were qualitatively similar, but less pronounced in male experimental animals (data not shown)," (29) suggesting that these mice may also have shown sexual dimorphism in response to removal of the IGF-1 receptor on OCN+ cells. On the other hand, the phenotype we observed may be independent of sex hormones or insulin based on the work by Goring and colleagues, who found that conditional disruption of VEGF in OCN-expressing cells in mice exerts a divergent influence on morphological, cellular, and whole-bone properties between sexes; furthermore, they describe that the underlying sexual divergence in VEGF signaling in osteoblast cultures in vitro is independent of circulating sex hormones.…”

Section: Discussionmentioning

confidence: 94%

“…DT‐treated mice exhibited changes in their blood sera lipid and protein profiles. In both males and females, there was a highly significant—nearly fourfold—increase in ECM1, which is expressed in many tissues including chondrocytes, and has been shown to regulate endochondral bone formation ( 30 ) and angiogenesis. ( 31 ) Overexpression of ECM1 via tissue‐specific transgene expression indicates that it inhibits both osteoblast and chondrocyte function; reduced bone parameters are seen in osteoblast‐specific overexpression models and growth plate abnormalities are seen in transgenic mice with chondrocyte‐specific overexpression.…”

Section: Discussionmentioning

confidence: 99%

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Targeting Bone Cells During Sexual Maturation Reveals Sexually Dimorphic Regulation of Endochondral Ossification

et al. 2020

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In endochondral ossification, chondroblasts become embedded in their matrix and become chondrocytes, which are mature cells that continue to proliferate, eventually becoming hypertrophic. Hypertrophic chondrocytes produce cartilage that is then resorbed by osteoclasts prior to bone matrix replacement via osteoblasts. Although sexually dimorphic bone phenotypes have long been characterized, specific modulation of the growth plate during a critical window in sexual maturation has not been evaluated. Here we report that specific depletion of osteocalcin-(OCN-) expressing cells in vivo during sexual maturation leads to dimorphic bone phenotypes in males and females. At 6 to 8 weeks of age, OCN-Cre;iDTR (inducible diphtheria toxin receptor-expressing) mice were treated with diphtheria toxin (DT) for 2 weeks to deplete OCN+ cells. At the end of the study, long bones were collected for μCT and histomorphometry, and serum was collected for proteomic and lipidomic analyses. Ablation of OCN+ cells in mice leads to consistent trends for weight loss after 2 weeks of treatment. Females exhibited decreased skeletal parameters in response to OCN+ cell ablation treatment, as expected. However, OCN+ cell ablation in males uniquely displayed an expansion of hypertrophic chondrocytes, a widening of the growth plate, and an abnormal "clubbing" anatomy of the distal femur. Following DT treatment, mice from both sexes also underwent metabolic cage analysis, in which both sexes exhibited decreased energy expenditure. We conclude that skewing endochondral bone formation during longitudinal growth has a profound effect on body weight and energy expenditure with sex-specific effects on developing bone.

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

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Targeting Bone Cells During Sexual Maturation Reveals Sexually Dimorphic Regulation of Endochondral Ossification

et al. 2020

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“…Importance of morphological factors for chronic musculoskeletal pain was also demonstrated by revealing of GIP1associated genes SLC39A8 and ECM1, which are known to be implicated in the development and functioning of the musculoskeletal system. ECM1 gene encodes a negative regulator of bone mineralization and chondrogenesis [51][52][53] . GIP1-associated ("pain-promoting") variant in this gene showed an association with the increased level of ECM1 protein in our SMR/HEIDI analysis.…”

Section: Discussionmentioning

confidence: 99%

Analysis of genetically independent phenotypes identifies shared genetic factors associated with chronic musculoskeletal pain conditions

et al. 2020

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Chronic musculoskeletal pain affects all aspects of human life. However, mechanisms of its genetic control remain poorly understood. Genetic studies of pain are complicated by the high complexity and heterogeneity of pain phenotypes. Here, we apply principal component analysis to reduce phenotype heterogeneity of chronic musculoskeletal pain at four locations: the back, neck/shoulder, hip, and knee. Using matrices of genetic covariances, we constructed four genetically independent phenotypes (GIPs) with the leading GIP (GIP1) explaining 78.4% of the genetic variance of the analyzed conditions, and GIP2-4 explain progressively less. We identified and replicated five GIP1-associated loci and one GIP2associated locus and prioritized the most likely causal genes. For GIP1, we showed enrichment with multiple nervous system-related terms and genetic correlations with anthropometric, sociodemographic, psychiatric/personality traits and osteoarthritis. We suggest that GIP1 represents a biopsychological component of chronic musculoskeletal pain, related to physiological and psychological aspects and reflecting pain perception and processing.

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“…PGRN is known to promote chondrogenesis under physiological conditions . To determine whether PGRN‐mediated chondrogenesis contributes to PGRN‐stimulated diabetic fracture healing, we established a closed fracture mouse model (also called the Bonnarens and Einhorn model), in diabetic WT mice, followed by local delivery of collagen sponge containing PGRN or PBS.…”

Section: Resultsmentioning

confidence: 99%

Progranulin promotes diabetic fracture healing in mice with type 1 diabetes

Wei

Zhang

Ding

et al. 2019

Annals of the New York Academy of Sciences

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Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by insulin deficiency, and patients with diabetes have an increased risk of bone fracture and significantly impaired fracture healing. Proinflammatory cytokine tumor necrosis factor‐alpha is significantly upregulated in diabetic fractures and is believed to underlie delayed fracture healing commonly observed in diabetes. Our previous genetic screen for the binding partners of progranulin (PGRN), a growth factor‐like molecule that induces chondrogenesis, led to the identification of tumor necrosis factor receptors (TNFRs) as the PGRN‐binding receptors. In this study, we employed several in vivo models to ascertain whether PGRN has therapeutic effects in diabetic fracture healing. Here, we report that deletion of PGRN significantly delayed bone fracture healing and aggravated inflammation in the fracture models of mice with T1DM. In contrast, recombinant PGRN effectively promoted diabetic fracture healing by inhibiting inflammation and enhancing chondrogenesis. In addition, both TNFR1 proinflammatory and TNFR2 anti‐inflammatory signaling pathways are involved in PGRN‐stimulated diabetic fracture healing. Collectively, these findings illuminate a novel understanding concerning the role of PGRN in diabetic fracture healing and may have an application in the development of novel therapeutic intervention strategies for diabetic and other types of impaired fracture healing.

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Extracellular matrix protein 1, a direct targeting molecule of parathyroid hormone‐related peptide, negatively regulates chondrogenesis and endochondral ossificationviaassociating with progranulin growth factor

Cited by 22 publications

References 55 publications

Targeting Bone Cells During Sexual Maturation Reveals Sexually Dimorphic Regulation of Endochondral Ossification

Targeting Bone Cells During Sexual Maturation Reveals Sexually Dimorphic Regulation of Endochondral Ossification

Analysis of genetically independent phenotypes identifies shared genetic factors associated with chronic musculoskeletal pain conditions

Progranulin promotes diabetic fracture healing in mice with type 1 diabetes

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