Calcium signaling leads to mitochondrial depolarization in impact‐induced chondrocyte death in equine articular cartilage explants

Huser, Camille; Davies, Malcolm

doi:10.1002/art.22717

Cited by 77 publications

(63 citation statements)

References 71 publications

(57 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This signal transduction chain is in keeping with a recent publication (48) that reports a key role for L-type voltage-gated channels in osteoarthritis, evoked and aggravated by mechanical trauma. We consider it an appealing possibility that the chondrocytic Ca 2+ signal of cartilage traumatic injury impacts chondrocytes' cytoskeleton, energy homeostasis, apoptotic equilibrium, and inflammatory phenotype (15,(62)(63)(64)(65).…”

Section: Discussionmentioning

confidence: 99%

Synergy between Piezo1 and Piezo2 channels confers high-strain mechanosensitivity to articular cartilage

Lee¹,

Leddy²,

Chen³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

367

348

View full text Add to dashboard Cite

Diarthrodial joints are essential for load bearing and locomotion. Physiologically, articular cartilage sustains millions of cycles of mechanical loading. Chondrocytes, the cells in cartilage, regulate their metabolic activities in response to mechanical loading. Pathological mechanical stress can lead to maladaptive cellular responses and subsequent cartilage degeneration. We sought to deconstruct chondrocyte mechanotransduction by identifying mechanosensitive ion channels functioning at injurious levels of strain. We detected robust expression of the recently identified mechanosensitive channels, PIEZO1 and PIEZO2. Combined directed expression of Piezo1 and -2 sustained potentiated mechanically induced Ca 2+ signals and electrical currents compared with single-Piezo expression. In primary articular chondrocytes, mechanically evoked Ca 2+ transients produced by atomic force microscopy were inhibited by GsMTx4, a PIEZO-blocking peptide, and by Piezo1-or Piezo2-specific siRNA. We complemented the cellular approach with an explant-cartilage injury model. GsMTx4 reduced chondrocyte death after mechanical injury, suggesting a possible therapy for reducing cartilage injury and posttraumatic osteoarthritis by attenuating Piezo-mediated cartilage mechanotransduction of injurious strains.A rticular cartilage is a hydrated connective tissue that supports loads and minimizes friction in the diarthrodial joints. It has a highly differentiated extracellular matrix (ECM) composed primarily of type II collagen, the large aggregating proteoglycan, aggrecan, and water. Chondrocytes are the only cells in cartilage and are responsible for maintaining and remodeling cartilage through a homeostatic balance of anabolic and catabolic activities. Under normal physiologic conditions, chondrocytes are exposed to millions of cycles of mechanical loading per year (1). These mechanical signals play an important role in regulating chondrocyte anabolic and biosynthetic activity, as evidenced by cartilage atrophy following periods of disuse or immobilization (2-7). However, under abnormal loading conditions (e.g., due to obesity, trauma, or joint instability), mechanical factors play a critical role in the onset and progression of osteoarthritis (1). Such "injurious" loading has been modeled in vitro using explant culture systems that replicate many of the early cellular and molecular events characteristic of osteoarthritis (8). Osteoarthritis is a painful and debilitating disease of weight-bearing joints that affects over 26 million people in the United States (9) with posttraumatic arthritis being responsible for ∼12% of the incidence of osteoarthritis (10).Despite the critical importance of mechanical loading in health and disease of synovial joints, the mechanisms of mechanotransduction of chondrocytes are not fully understood and are likely to differ under physiologic and pathologic conditions (11)(12)(13)(14). Although many different mechanisms have been shown to be involved in chondrocyte mechanotransduction (13,(15)(16)(17), recent st...

show abstract

Section: Discussionmentioning

confidence: 99%

Synergy between Piezo1 and Piezo2 channels confers high-strain mechanosensitivity to articular cartilage

Lee¹,

Leddy²,

Chen³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

367

348

View full text Add to dashboard Cite

show abstract

“…The presence of calcium in Hartmann's solution is believed to support chondrocyte metabolism better than solutions without added calcium such as 0.9% saline, which have been considered unphysiologic [18]. However, recent work suggests a reduction in calcium in the extracellular medium also decreases chondrocyte death after mechanical injury, possibly through the prevention of an increase in cytoplasmic calcium [10]. We suggest the greater chondrocyte death associated with Hartmann's solution compared with 0.9% saline is not only the result of the lower osmolarity of the Hartmann's solution, but also the result of the calcium present in its preparations.…”

Section: Discussionmentioning

confidence: 99%

“…The composition of irrigation solutions normally used in vivo during articular surgery is different. Articular cartilage is a complex, heterogenous, viscoelastic, anisotropic tissue in which the osmotic sensitivity of in situ chondrocytes varies depending on the composition of the extracellular medium [5,6,10,14,15,23,24]. Therefore, to determine whether varying the osmolarity of an extracellular medium is relevant clinically, it is essential to establish that the spatial distribution of chondrocyte death and the responses of in situ chondrocytes to mechanical injury following alterations in the extracellular osmolarity previously observed in experiments using standard culture media, can be reproduced using joint irrigation solutions normally used during open and arthroscopic articular surgery.…”

Section: Introductionmentioning

confidence: 99%

Increasing the Osmolarity of Joint Irrigation Solutions May Avoid Injury to Cartilage: A Pilot Study

Amin

Huntley

Simpson

et al. 2010

Clinical Orthopaedics &Amp; Related Research

View full text Add to dashboard Cite

Saline (0.9%, 285 mOsm) and Hartmann's solution (255 mOsm) are two commonly used joint irrigation solutions that alter the extracellular osmolarity of in situ chondrocytes during articular surgery. We asked whether varying the osmolarity of these solutions influences in situ chondrocyte death in mechanically injured articular cartilage. We initially exposed osteochondral tissue harvested from the metacarpophalangeal joints of 3-year-old cows to solutions of 0.9% saline and Hartmann's solution of different osmolarity (100-600 mOsm) for 2 minutes to allow in situ chondrocytes to respond to the altered osmotic environment. The full thickness of articular cartilage then was ''injured'' with a fresh scalpel. Using confocal laser scanning microscopy, in situ chondrocyte death at the injured cartilage edge was quantified spatially as a function of osmolarity at 2.5 hours. Increasing the osmolarity of 0.9% saline and Hartmann's solution to 600 mOsm decreased in situ chondrocyte death in the superficial zone of injured cartilage. Compared with 0.9% saline, Hartmann's solution was associated with greater chondrocyte death in the superficial zone of injured cartilage, but not when the osmolarity of both solutions was increased to 600 mOsm. These experiments may have implications for the design of irrigation solutions used during arthroscopic and open articular surgery.

show abstract

“…In general, calcium transients lead to activation of signaling via both calmodulin kinase and calcineurin/NFAT pathways (41, 42) among others. Although these pathways are known to be important in the modulation of both chondrogenesis and chondrocyte differentiation (43,44), work remains to fully characterize how calcium signaling in chondrocytes contributes to the anabolic or catabolic effects of mechanical stress.…”

Section: Effects Of Stress On Chondrogenesis and Endochondral Ossificmentioning

confidence: 99%

Regulation of chondrogenesis and chondrocyte differentiation by stress

Zuscik¹,

Hilton²,

Zhang³

et al. 2008

J. Clin. Invest.

216

173

View full text Add to dashboard Cite

Chondrogenesis and endochondral ossification are the cartilage differentiation processes that lead to skeletal formation and growth in the developing vertebrate as well as skeletal repair in the adult. The exquisite regulation of these processes, both in normal development and in pathologic situations, is impacted by a number of different types of stress. These include normal stressors such as mechanical loading and hypoxia as well pathologic stressors such as injury and/or inflammation and environmental toxins. This article provides an overview of the processes of chondrogenesis and endochondral ossification and their control at the molecular level. A summary of the influence of the most well-understood normal and pathologic stressors on the differentiation program is also presented. Introduction to cartilageCartilage is a connective tissue that is comprised primarily of matrix (mainly collagens and proteoglycans) containing relatively sparse populations of chondrocytes, which perform matrix-generation and maintenance functions. During the development and growth of vertebrates, chondrogenesis is the dynamic cellular process that leads to the establishment of various types of cartilage, including hyaline, fibrous, and elastic cartilage. Hyaline cartilage is found in craniofacial structures, the trachea and bronchial tubes, the articular surfaces of diarthrodial joints, and the growth plate (GP) of long bones. GPs are responsible for driving the process of limb lengthening and bone growth during development pre- and postnatally. This type of bone growth involves the process of endochondral ossification (otherwise known as bone formation). The type of cartilage that is most prominent and most susceptible to both normal and pathologic forms of stress is the hyaline cartilage of the limb and trunk skeleton, which originates from the differentiation of condensed mesenchymal cells into clusters of cartilage cells known as chondrocytes. These cartilage anlagen preform the skeleton and provide a framework for endochondral bone development, a process that involves chondrocyte maturation and matrix mineralization in the GPs. The cells of each skeletal element proceed through a multi-step differentiation process generating both the mature GP cartilage, which controls skeletal growth during early and adolescent development, and the permanent articular cartilage (AC) found at the joint surface of all long bones.The processes of chondrogenesis and endochondral bone formation are not restricted to the developing skeletal system. In fact, following stress-related injuries, such as fractures of endochondral bone, the developmental programs of chondrogenesis and chondrocyte proliferation, maturation, hypertrophy, and terminal differentiation are reinitiated at the site of injury. Additionally, stress-related cartilage diseases such as osteoarthritis (OA) also have marked effects on the differentiation and maintenance of AC during adult life. This is why much attention has been paid to studying the cellular and molecular mechanism...

show abstract

Calcium signaling leads to mitochondrial depolarization in impact‐induced chondrocyte death in equine articular cartilage explants

Cited by 77 publications

References 71 publications

Synergy between Piezo1 and Piezo2 channels confers high-strain mechanosensitivity to articular cartilage

Synergy between Piezo1 and Piezo2 channels confers high-strain mechanosensitivity to articular cartilage

Increasing the Osmolarity of Joint Irrigation Solutions May Avoid Injury to Cartilage: A Pilot Study

Regulation of chondrogenesis and chondrocyte differentiation by stress

Contact Info

Product

Resources

About