Prevention of Injury-Induced Osteoarthritis in Rodent Temporomandibular Joint by Targeting Chondrocyte CaSR

Abstract

Traumatic joint injuries produce osteoarthritic cartilage manifesting accelerated chondrocyte terminal differentiation and matrix degradation via unknown cellular and molecular mechanisms. Here we report the ability of biomechanical stress to increase expression of the calcium‐sensing receptor (CaSR), a pivotal driver of chondrocyte terminal differentiation, in cultured chondrogenic cells subjected to fluid flow shear stress (FFSS) and in chondrocytes of rodent temporomandibular joint (TMJ) cartilage subjected to unilateral anterior cross‐bite (UAC). In cultured ATDC5 cells or TMJ chondrocytes, FFSS induced Ca2+ loading and CaSR localization in endoplasmic reticulum (ER), casually accelerating cell differentiation that could be abrogated by emptying ER Ca2+ stores or CaSR knockdown. Likewise, acute chondrocyte‐specific Casr knockout (KO) prevented the UAC‐induced acceleration of chondrocyte terminal differentiation and matrix degradation in TMJ cartilage in mice. More importantly, local injections of CaSR antagonist, NPS2143, replicated the effects of Casr KO in preventing the development of osteoarthritic phenotypes in TMJ cartilage of the UAC‐treated rats. Our study revealed a novel pathological action of CaSR in development of osteoarthritic cartilage due to aberrant mechanical stimuli and supports a therapeutic potential of calcilytics in preventing osteoarthritis in temporomandibular joints by targeting the CaSR. © 2018 American Society for Bone and Mineral Research.

International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function

“…In a dental malocclusion model affecting the temporomandibular joint in rats, increased expression of CaSR in articular chondrocytes and in the endoplasmic reticulum of these cells was also observed (Zhang et al, 2019). These provided some evidence to support a role for endoplasmic reticulum expressed CaSR, as opposed to cell membrane CaSR in chondrocytes under stress (Zhang et al, 2019). Increased whole-cell CaSR and increased endoplasmic reticulum CaSR were also observed in vitro using articular cartilage chondrocytes exposed to shear stress (Zhang et al, 2019).…”

“…The authors proposed a role for increased Ca 2+ o and the CaSR in intervertebral disc degeneration (Grant et al, 2016). In a dental malocclusion model affecting the temporomandibular joint in rats, increased expression of CaSR in articular chondrocytes and in the endoplasmic reticulum of these cells was also observed (Zhang et al, 2019). These provided some evidence to support a role for endoplasmic reticulum expressed CaSR, as opposed to cell membrane CaSR in chondrocytes under stress (Zhang et al, 2019).…”

Irisin Mitigates Oxidative Stress, Chondrocyte Dysfunction and Osteoarthritis Development through Regulating Mitochondrial Integrity and Autophagy

“…The loss of endoplasmic reticulum (ER) chaperones increase ER stress, downregulating cartilage ECM synthesis in osteoarthritic joints [10]. Increased ER stress is present in articular chondrocytes in unilateral anterior cross-bite-mediated OA in mice [11]. The downregulation of ER stress through activating eukaryotic translation initiation factor 2α compromises OA signs, such as cartilage damage, synovium remodeling and osteophyte formation, in anterior cruciate ligament transection-mediated joint injury upon mechanical loading [12].…”

Positive Feedback Regulation Between USP15 and ERK2 Promotes Cartilage Repair in Experimental Osteoarthritis

“…OA is the most common type of arthritis with in ammatory disease in the synovial joints (32,33) . It is characterized by gradual degeneration of articular cartilage and changes in the structure and function of the entire joint (34,35) .…”