Endoplasmic Reticulum Stress and Unfolded Protein Response in Cartilage Pathophysiology; Contributing Factors to Apoptosis and Osteoarthritis

Hughes, Alexandria; Oxford, Alexandra E.; Tawara, Ken; Jorcyk, Cheryl L.; Oxford, Julia

doi:10.3390/ijms18030665

Cited by 81 publications

(66 citation statements)

References 113 publications

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“…It is possible that conjugation of Ufm1 to Ddrgk1 protects it during ER stress and Ddrgk1 in turn stabilizes other proteins like Sox9 however further studies are needed to determine this. Many chondrodysplasias result from the inability of chondrocytes or osteoblasts to deal with increasing load in the ER, be it due to mutations in the ER machinery or mutations of ECM structural proteins resulting in their misfolding [16]. Many affected by these disorders develop OA as a secondary consequence.…”

Section: Discussionmentioning

confidence: 99%

“…The relative expression of Runx2, Osterix, Osteocalcin and Col1a1 were measured in the 2T3 culture system as the markers of osteogenic differentiation [7]. Bip expression was also measured as its expression is known to increase during osteogenic differentiation as well as during ER stress [6]. We found that Ufsp2, Uba5 (E1), Ufl1 (E3), Ddrgk1 and Lzap were all significantly upregulated in the induced cultures relative to the control at day 8.…”

Section: Ufm1 System and Osteogenic Differentiationmentioning

confidence: 91%

“…Chondrocytes and osteoblasts actively secrete the proteins that form the vast extracellular matrix of cartilage and bone. Forms of skeletal dysplasia caused by mutations in matrix genes have been identified where ER stress is a common feature of their molecular pathology [5,6].…”

Section: Introductionmentioning

confidence: 99%

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The Ufm1 system is upregulated by ER stress during osteogenic differentiation

Dudek

2019

Preprint

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Objective: Mutations in the catalytic site of the ubiquitin-fold modifier 1(UFM1)-specific peptidase 2 (UFSP2) gene have been identified to cause autosomal dominant Beukes hip dysplasia in a large multigenerational family and a novel form of autosomal dominant spondyloepimetaphyseal dysplasia in a second family. We investigated the expression of the UFSP2/UFM1 system during mouse joint development the connection to ER stress induced during osteogenic differentiation. Methods:The pattern of expression of Ufsp2 was determined by radioactive RNA in situ hybridisation on mouse tissue sections. qPCR was used to monitor expression during in vitro osteogenic differentiation and chemically induced ER stress. Affinity purification and mass spectrometry was used for isolation and identification of Ufm1 conjugation targets. Luciferase reporter assay was used to investigate the activity of Ufm1 system genes' promoters. Results:We found that Ufsp2 was predominantly expressed in the bone and secondary ossification centres of 10-day old mice. The Ufm1 system was upregulated during in vitro osteogenic differentiation and in response to chemically induced ER stress. We identified unfolded protein response elements in the upstream sequences of Uba5, Ufl1, Ufm1and Lzap. We identified putative Ufm1 conjugation targets where conjugation was increased in response to ER stress. Conclusion:Higher expression of Ufsp2 in bone and secondary ossification centres as well as upregulation of components of the Ufm1system in response to ER stress suggests that the molecular pathway between the UFSP2 mutations and form of skeletal dysplasia may relate to abnormal ER stress responses during osteoblast differentiation.

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Section: Discussionmentioning

confidence: 99%

Section: Ufm1 System and Osteogenic Differentiationmentioning

confidence: 91%

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The Ufm1 system is upregulated by ER stress during osteogenic differentiation

Dudek

2019

Preprint

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“…For example, loss of function mutations in PERK, one of the sensors of ER stress, underlie the multiple abnormalities seen in patients with Wolcott‐Rallison syndrome, including short stature, low bone mass, neuromotor defects, hepatic and renal failure secondary to early‐onset diabetes mellitus . Skeletal disease often involves alterations in redox status, hypoxia, and other factors that could alter protein folding . These conditions could induce ER stress and the UPR in bone cells, particularly matrix synthesizing osteoblasts, and osteocytes, which secrete a variety of factors, involved in control of bone formation and resorption .…”

Section: Introductionmentioning

confidence: 99%

Elevation of the unfolded protein response increases RANKL expression

et al. 2020

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Increased production of the osteoclastogenic cytokine RANKL is a common feature of pathologic bone loss, but the underlying cause of this increase is poorly understood. The unfolded protein response (UPR) is activated in response to accumulation of misfolded proteins in the endoplasmic reticulum (ER). Failure to resolve misfolding results in excess UPR signaling that stimulates cytokine production and cell death. We therefore investigated whether RANKL is one of the cytokines stimulated in response to elevated UPR in bone cells. Pharmacologic induction of UPR with tunicamycin (Tm)‐stimulated RANKL expression in cultures of primary osteoblastic cells and in osteoblast and osteocyte cell lines. Pharmacologic inhibition of the UPR blunted Tm‐induced RANKL production. Silencing Edem1 or Sel1l, proteins that aid in degradation of misfolded proteins, also induced UPR and increased RANKL mRNA. Moreover, Tm or hypoxia increased RANKL and bone resorption in cultures of neonatal murine calvaria. Administration of Tm to adult mice caused dilation of ER in osteoblasts and osteocytes, elevated the UPR, and increased RANKL expression and osteoclast number. These findings support the hypothesis that excessive UPR signaling stimulates the expression of RANKL by osteoblasts and osteocytes, and thereby facilitates excessive bone resorption and bone loss in pathologic conditions.

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“…The cellular response mechanisms that underlie intrinsic cartilage and subchondral bone repair after joint injury are poorly understood, although it is now clear that they cannot be delineated under the simplistic paradigm of a balance of matrix anabolism versus catabolism. [1][2][3][4] Therefore, the discovery of new targetable disease mechanisms is essential to the design of effective biological therapies to complement existing strategies for osteoarthritis (OA) prevention in the clinic. With respect to post-traumatic OA, the cellular reaction to joint tissue injury can be viewed as a classical "wound-healing" response, involving a balance between "inflammatory/fibrotic" and "chondrogenic/osteogenic" pathways in the injured joint environment.…”

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confidence: 99%

Pirfenidone reduces subchondral bone loss and fibrosis after murine knee cartilage injury

Chan

Luo

et al. 2017

Journal Orthopaedic Research

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Pirfenidone is an anti-inflammatory and anti-fibrotic drug that has shown efficacy in lung and kidney fibrosis. Because inflammation and fibrosis have been linked to the progression of osteoarthritis, we investigated the effects of oral Pirfenidone in a mouse model of cartilage injury, which results in chronic inflammation and joint-wide fibrosis in mice that lack hyaluronan synthase 1 (Has1 ) in comparison to wild-type. Femoral cartilage was surgically injured in wild-type and Has1 mice, and Pirfenidone was administered in food starting after 3 days. At 4 weeks, Pirfenidone reduced the appearance, on micro-computed tomography, of pitting in subchondral bone at, and cortical bone surrounding, the site of cartilage injury. This corresponded with a reduction in fibrotic tissue deposits as observed with gross joint surface photography. Pirfenidone resulted in significant recovery of trabecular bone parameters affected by joint injury in Has1 mice, although the effect in wild-type was less pronounced. Pirfenidone also increased Safranin-O staining of growth plate cartilage after cartilage injury and sham operation in both genotypes. Taken together with the expression of selected extracellular matrix, inflammation, and fibrosis genes, these results indicate that Pirfenidone may confer chondrogenic and bone-protective effects, although the well-known anti-fibrotic effects of Pirfenidone may occur earlier in the wound-healing response than the time point examined in this study. Further investigations to identify the specific cell populations in the joint and signaling pathways that are responsive to Pirfenidone are warranted, as Pirfenidone and other anti-fibrotic drugs may encourage tissue repair and prevent progression of post-traumatic osteoarthritis. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:365-376, 2018.

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Endoplasmic Reticulum Stress and Unfolded Protein Response in Cartilage Pathophysiology; Contributing Factors to Apoptosis and Osteoarthritis

Cited by 81 publications

References 113 publications

The Ufm1 system is upregulated by ER stress during osteogenic differentiation

The Ufm1 system is upregulated by ER stress during osteogenic differentiation

Elevation of the unfolded protein response increases RANKL expression

Pirfenidone reduces subchondral bone loss and fibrosis after murine knee cartilage injury

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