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

Novince, Chad M.; Koh, Amy J.; Michalski, Megan N.; Marchesan, Julie T.; Wang, Jason; Jung, Younghun; Berry, Janice E.; Eber, Matthew R.; Rosol, Thomas J.; Taichman, Russell S.; McCauley, Laurie K.

doi:10.1016/j.ajpath.2011.07.032

Cited by 21 publications

(18 citation statements)

References 65 publications

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“…The lower SDF1 expression correlated well with decreased PRG4 expression in tendons of old rats. It was previously reported that SDF1 mRNA expression was decreased in bone marrow of PRG4 knockout mice (Novince et al 2011), suggesting that PRG4 could be involved in the regulation of SDF1 expression. Decreased SDF1 expression in tendons of old rats could impact the function of tendon-derived stem/progenitor cells and/or tendon regenerative capacity.…”

Section: Discussionmentioning

confidence: 88%

Age-related changes in structure and extracellular matrix protein expression levels in rat tendons

Kostrominova

Brooks

2013

AGE

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The musculoskeletal system (muscle-tendonbone) demonstrates numerous age-related changes, with modifications in tendons the least well studied, although increased predisposition to tendinopathy and rupture have been reported. In order to gain insights into the basis of age-associated increase in tendon injuries, we compared Achilles and tibialis anterior tendons and myotendinous junctions (MTJs) from 3-to 5-and 22-to 25-month-old rats for underlying structure and composition. Significant decreases were observed by qRT-PCR for collagen I, III, and V mRNA expression in tendons of old rats, but immunostaining detected no apparent differences in collagen I and V expression on the protein level. Tendons of old compared with young rats had decreased mRNA expression levels of proteoglycan 4 (PRG4) and elastin (Eln), but no differences in the mRNA expression of connective tissue growth factor, TGF-beta 1, or stromal cell-derived factor 1. For PRG4, immunostaining showed good correlation with qRT-PCR results. This is the first study to show reductions in PRG4 in tendons and MTJs of old rats. Decreased PRG4 expression in tendons could result in increased tendon stiffness and may be associated with decreased activity in the elderly. The diminished collagen mRNA expression in combination with decreased PRG4 and Eln mRNA expression may be associated with increased risk of tendon injury with aging.

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Section: Discussionmentioning

confidence: 88%

Age-related changes in structure and extracellular matrix protein expression levels in rat tendons

Kostrominova

Brooks

2013

AGE

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“…(12,13) Although most studies of Prg4 have focused on the role of the Prg4 gene product lubricin and joint function, we hypothesized that proteoglycan 4 also plays a role in skeletal development and remodeling based upon Prg4 expression in bone (11) and the noted osteopenic phenotype in the Prg4 mutant mouse. (12) Furthermore, our findings that Prg4 is a PTH-responsive gene in bone (10) lead us to speculate that proteoglycan 4 supports the anabolic actions of PTH in the skeleton.…”

Section: Discussionmentioning

confidence: 88%

“…Proteoglycan 4 ( Prg4 ), a novel PTH responsive gene in bone, (9,10) is a strong candidate regulator of the anabolic actions of PTH. The Prg4 gene encodes an approximately 345-kD proteoglycan, consisting of 1404 amino acids spanning 12 exons.…”

Section: Introductionmentioning

confidence: 99%

“…(12) Of interest, osteopenia has been noted in microradiographs of joints from Prg4 mutant mice. (12) Whereas studies have shown that Prg4 is endogenously expressed in bone (11) and Prg4 is a PTH responsive gene in the bone marrow in vivo and isolated osteoblastic cells in vitro, (10) there have been no reported investigations of the actions of proteoglycan 4 in bone. The purpose of this study was to investigate the role of proteoglycan 4 as a regulator of skeletal development, remodeling, and PTH anabolic actions.…”

Section: Introductionmentioning

confidence: 99%

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

Novince

Michalski

Koh

et al. 2011

Journal of Bone and Mineral Research

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Proteoglycan 4 (Prg4), known for its lubricating and protective actions in joints, is a strong candidate regulator of skeletal homeostasis and parathyroid hormone (PTH) anabolism. Prg4 is a PTH-responsive gene in bone and liver. Prg4 null mutant mice were used to investigate the impact of proteoglycan 4 on skeletal development, remodeling, and PTH anabolic actions. Young Prg4 mutant and wild-type mice were administered intermittent PTH(1–34) or vehicle daily from 4 to 21 days. Young Prg4 mutant mice had decreased growth plate hypertrophic zones, trabecular bone, and serum bone formation markers versus wild-type mice, but responded with a similar anabolic response to PTH. Adult Prg4 mutant and wild-type mice were administered intermittent PTH(1–34) or vehicle daily from 16 to 22 weeks. Adult Prg4 mutant mice had decreased trabecular and cortical bone, and blunted PTH-mediated increases in bone mass. Joint range of motion and animal mobility were lower in adult Prg4 mutant versus wild-type mice. Adult Prg4 mutant mice had decreased marrow and liver fibroblast growth factor 2 (FGF-2) mRNA and reduced serum FGF-2, which were normalized by PTH. A single dose of PTH decreased the PTH/PTHrP receptor (PPR), and increased Prg4 and FGF-2 to a similar extent in liver and bone. Proteoglycan 4 supports endochondral bone formation and the attainment of peak trabecular bone mass, and appears to support skeletal homeostasis indirectly by protecting joint function. Bone- and liver-derived FGF-2 likely regulate proteoglycan 4 actions supporting trabeculae formation. Blunted PTH anabolic responses in adult Prg4 mutant mice are associated with altered biomechanical impact secondary to joint failure.

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“…As PTH increases BM SDF-1 (Jung et al, 2006), it potentially suppresses peripheral neutrophils. Indeed, Novince and co-workers observed decreased peripheral neutrophils in PRG4-deficient mice on PTH therapy (Novince et al, 2011). Thus, intermittent PTH likely possesses anti-inflammatory and/or pro-resolution effects in osseous wounds.…”

Section: Discussionmentioning

confidence: 99%

Intra-oral PTH Administration Promotes Tooth Extraction Socket Healing

et al. 2013

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Intermittent parathyroid hormone (PTH) administration increases systemic and craniofacial bone mass. However, the effect of PTH therapy on healing of tooth extraction sites is unknown. The aims of this study were to determine the effect of PTH therapy on tooth extraction socket healing and to examine whether PTH intra-oral injection promotes healing. The mandibular first molars were extracted in rats, and subcutaneous PTH was administered intermittently for 7, 14, and 28 days. In a second study, maxillary second molars were extracted, and PTH was administered by either subcutaneous or intra-oral injection to determine the efficacy of intra-oral PTH administration. Healing was assessed by micro-computed tomography and histomorphometric analyses. PTH therapy accelerated the entire healing process and promoted both hard-and softtissue healing by increasing bone fill and connective tissue maturation. PTH therapy by intra-oral injection was as effective as subcutaneous injection in promoting tooth extraction socket healing. The findings suggest that PTH therapy promotes tooth extraction socket healing and that intra-oral injections can be used to administer PTH. A supplemental appendix to this article is published electronically only at http://jdr.sagepub.com/supplemental.

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

Cited by 21 publications

References 65 publications

Age-related changes in structure and extracellular matrix protein expression levels in rat tendons

Age-related changes in structure and extracellular matrix protein expression levels in rat tendons

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

Intra-oral PTH Administration Promotes Tooth Extraction Socket Healing

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