Proteoglycan 4: A dynamic regulator of skeletogenesis and parathyroid hormone skeletal anabolism

Novince, Chad M.; Michalski, Megan N.; Koh, Amy J.; Sinder, Benjamin P.; Entezami, Payam; Eber, Matthew R.; Pettway, Glenda J.; Rosol, Thomas J.; Wronski, Thomas J.; Kozloff, Ken; McCauley, Laurie K.

doi:10.1002/jbmr.508

Cited by 41 publications

(58 citation statements)

References 61 publications

(93 reference statements)

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“…Based on reports that Prg4 is expressed in bone 20 and radiographic findings that Prg4 −/− mice and humans afflicted by CACP have periarticular osteopenia 1,6 , micro-CT analysis was employed to assess subchondral bone morphology in the distal femur of Prg4 −/− mice (Fig. 6).…”

Section: Resultsmentioning

confidence: 99%

Impact of proteoglycan‐4 and parathyroid hormone on articular cartilage

Novince

Entezami

Wilson

et al. 2012

Journal Orthopaedic Research

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Proteoglycan-4 (Prg4) protects synovial joints from arthropathic changes by mechanisms that are incompletely understood. Parathyroid hormone (PTH), known for its anabolic actions in bone, increases Prg4 expression and has been reported to inhibit articular cartilage degeneration in arthropathic joints. To investigate the effect of Prg4 and PTH on articular cartilage, 16-week-old Prg4 mutant and wildtype mice were treated with intermittent PTH (1–34) or vehicle control daily for six weeks. Analyses included histology of the knee joint, micro-CT of the distal femur, and serum biochemical analysis of type II collagen fragments (CTX-II). Compared to wildtype littermates, Prg4 mutant mice had an acellular layer of material lining the surfaces of the articular cartilage and menisci, increased articular cartilage degradation, increased serum CTX-II concentrations, decreased articular chondrocyte apoptosis, increased synovium SDF-1 expression, and irregularly contoured subchondral bone. PTH-treated Prg4 mutant mice developed a secondary deposit overlaying the acellular layer of material lining the joint surfaces, but PTH-treatment did not alter signs of articular cartilage degeneration in Prg4 mutant mice. The increased joint SDF-1 levels and irregular subchondral bone found in Prg4 mutant mice introduce novel candidate mechanisms by which Prg4 protects articular cartilage.

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Section: Resultsmentioning

confidence: 99%

Impact of proteoglycan‐4 and parathyroid hormone on articular cartilage

Novince

Entezami

Wilson

et al. 2012

Journal Orthopaedic Research

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“…The region of interest for histomorphometric analysis was limited to the secondary spongiosa. Analysis was initiated 150 μm distal to the growth plate, extending 1000 μm distally, and 50 μm from endocortical surfaces . Images were taken at ×200, acquired by Olympus BX61 microscope (Olympus America, Inc., Center Valley, PA, USA), and analyzed using Visiopharm software (Visiopharm, Hoersholm, Denmark).…”

Section: Methodsmentioning

confidence: 99%

“…Images were taken at ×200, acquired by Olympus BX61 microscope (Olympus America, Inc., Center Valley, PA, USA), and analyzed using Visiopharm software (Visiopharm, Hoersholm, Denmark). Data are reported in accordance with standardized nomenclature as previously described …”

Section: Methodsmentioning

confidence: 99%

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Specific Commensal Bacterium Critically Regulates Gut Microbiota Osteoimmunomodulatory Actions During Normal Postpubertal Skeletal Growth and Maturation

et al. 2020

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The commensal gut microbiota critically regulates immunomodulatory processes that influence normal skeletal growth and maturation. However, the influence of specific microbes on commensal gut microbiota osteoimmunoregulatory actions is unknown. We have shown previously that the commensal gut microbiota enhances TH17/IL17A immune response effects in marrow and liver that have procatabolic/antianabolic actions in the skeleton. Segmented filamentous bacteria (SFB), a specific commensal gut bacterium within phylum Firmicutes, potently induces TH17/IL17A‐mediated immunity. The study purpose was to delineate the influence of SFB on commensal gut microbiota immunomodulatory actions regulating normal postpubertal skeletal development. Two murine models were utilized: SFB‐monoassociated mice versus germ‐free (GF) mice and specific‐pathogen‐free (SPF) mice +/− SFB. SFB colonization was validated by 16S rDNA analysis, and SFB‐induced TH17/IL17A immunity was confirmed by upregulation of Il17a in ileum and IL17A in serum. SFB‐colonized mice had an osteopenic trabecular bone phenotype, which was attributed to SFB actions suppressing osteoblastogenesis and enhancing osteoclastogenesis. Intriguingly, SFB‐colonized mice had increased expression of proinflammatory chemokines and acute‐phase reactants in the liver. Lipocalin‐2 (LCN2), an acute‐phase reactant and antimicrobial peptide, was substantially elevated in the liver and serum of SFB‐colonized mice, which supports the notion that SFB regulation of commensal gut microbiota osteoimmunomodulatory actions are mediated in part through a gut–liver–bone axis. Proinflammatory TH17 and TH1 cells were increased in liver‐draining lymph nodes of SFB‐colonized mice, which further substantiates that SFB osteoimmune‐response effects may be mediated through the liver. SFB‐induction of Il17a in the gut and Lcn2 in the liver resulted in increased circulating levels of IL17A and LCN2. Recognizing that IL17A and LCN2 support osteoclastogenesis/suppress osteoblastogenesis, SFB actions impairing postpubertal skeletal development appear to be mediated through immunomodulatory effects in both the gut and liver. This research reveals that specific microbes critically impact commensal gut microbiota immunomodulatory actions regulating normal postpubertal skeletal growth and maturation. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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“…20,21 The PRG4 gene encodes an approximately 345-kDa proteoglycan, consisting of 1404 amino acids spanning 12 exons. PRG4 is expressed across skeletal and nonskeletal tissues, with highest relative levels of expression in articular joints, liver, and bone.…”

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confidence: 99%

Proteoglycan 4, a Novel Immunomodulatory Factor, Regulates Parathyroid Hormone Actions on Hematopoietic Cells

Novince¹,

Koh²,

Michalski³

et al. 2011

The American Journal of Pathology

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Proteoglycan 4 (PRG4), a critical protective factor in articular joints, is implicated in hematopoietic progenitor cell expansion and megakaryopoiesis. PRG4 loss-of-function mutations result in camptodactyly-arthropathy-coxa varapericarditis (CACP) syndrome, which is characterized primarily by precocious joint failure. PRG4 was identified as a novel parathyroid hormone (PTH) responsiveness gene in osteoblastic cells in bone, and was investigated as a potential mediator of PTH actions on hematopoiesis. Sixteen-week-old Prg4 ؊/؊ mutant and Prg4 ؉/؉ wild-type mice were treated daily with intermittent PTH (residues 1-34) or vehicle for 6 weeks. At 22 weeks of age, Prg4 mutant mice had increased peripheral blood neutrophils and decreased marrow B220 ؉ (B-lymphocytic) cells, which were normalized by PTH. The PTH-induced increase in marrow Lin ؊ Sca-1 ؉ c-Kit ؉ (hematopoietic progenitor) cells was blunted in mutant mice. Basal and PTHstimulated stromal cell-derived factor-1 (SDF-1) was decreased in mutant mice, suggesting SDF-1 as a candidate regulator of proteoglycan 4 actions on hematopoiesis in vivo. PTH stimulation of IL-6 mRNA was greater in mutant than in wild-type calvaria and bone marrow, suggesting a compensatory mechanism in the PTH-induced increase in marrow hematopoietic progenitor cells. In summary, proteoglycan 4 is a novel PTH-responsive factor regulating immune cells and PTH actions on marrow hematopoietic progenitor cells.

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Proteoglycan 4: A dynamic regulator of skeletogenesis and parathyroid hormone skeletal anabolism

Cited by 41 publications

References 61 publications

Impact of proteoglycan‐4 and parathyroid hormone on articular cartilage

Impact of proteoglycan‐4 and parathyroid hormone on articular cartilage

Specific Commensal Bacterium Critically Regulates Gut Microbiota Osteoimmunomodulatory Actions During Normal Postpubertal Skeletal Growth and Maturation

Proteoglycan 4, a Novel Immunomodulatory Factor, Regulates Parathyroid Hormone Actions on Hematopoietic Cells

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