The Homeostasis of Cartilage Matrix Remodeling and the Regulation of Volume-Sensitive Ion Channel

Abstract

Degenerative joint diseases of the hips and knees are common and are accompanied by severe pain and movement disorders. At the microscopic level, the main characteristics of osteoarthritis are the continuous destruction and degeneration of cartilage, increased cartilage extracellular matrix catabolism, decreased anabolism, increased synovial fluid, and decreased osmotic pressure. Cell volume stability is mainly regulated by ion channels, many of which are expressed in chondrocytes. These ion channels are closely related to pain regulation, volume regulation, the inflammatory response, cell proliferation, apoptosis, and cell differentiation. In this review, we focus on the important role of volume control-related ion channels in cartilage matrix remodeling and summarize current views. In addition, the potential mechanism of the volume-sensitive anion channel LRRC8A in the early occurrence of osteoarthritis is discussed.

Keywords: cell volume regulation; chondrocytes; ion channel; osteoarthritis.

Figure 1.

Radiographs and arthroscopy of osteoarthritis. A and B are anteroposterior and lateral radiographs, respectively. C and D are arthroscopy observations. A 57-year-old male patient came to see the doctor because a "sprain during exercise caused pain and discomfort in the left knee joint for one month." X-rays of the left knee showed narrowing of the medial space of the knee joint, hyperplasia of osteophytes, sclerosis of subchondral bone, and loose bodies in the intercondylar fossa. A CT scan was performed to further clarify the abovementioned lesions. Later, the patient underwent arthroscopic knee surgery. Intraoperative detection revealed that the cartilaginous surface of the left medial condyle of the femur and the medial plateau of the left tibia were severely damaged with arthritic synovial hyperplasia and a loose body in the intercondylar fossa. Red arrow: sclerosis of the subchondral bone in the left knee joint. Blue arrow: the internal joint space of the left knee is narrowed. White arrow: hyperplasia of osteophytes in the left knee joint.

Figure 2.

Continuous hypotonicity causes mitochondrial damage and cartilage matrix metabolism imbalance. When chondrocytes are in a hypotonic state for a long time, the imbalance of ATP-K and CLIC plasma channel function mediates the imbalance of mitochondrial volume regulation and fission and fusion in chondrocytes, leading to increased reactive oxygen species levels, mtDNA damage, chondrocyte apoptosis and inflammation. Eventually this leads to the destruction of the extracellular cartilage matrix.

Figure 3.

The process of inflammation caused by hypotonic cells. Extracellular hypotonicity activates ion channels on chondrocytes, increases the outflow of K⁺ and Cl^-, and modulates NLRP3 inflammasome and apoptosis-related dot-like protein ASC oligomerization, which induces the maturation of pro-caspase-1. Finally, mature caspase-1 induces the release of large amounts of IL-1β. At the same time, caspase-1 and caspase-4/5/11 specifically cleave GSDMD and trigger cell inflammation.

Figure 4.

Volume regulation of chondrocytes in physiological or pathological environments. First, under physiological conditions, the cartilage matrix is hydrated by mechanical loads such as exercise, and the osmotic pressure of synovial fluid is in a physiological state that regulates chondrocyte volume and maintains chondrocyte viability. Second, under physiological conditions, growth plate hypertrophic chondrocytes become physiologically enlarged, and endochondral ossification occurs. Third, in a pathological state, the synovial fluid is persistently hypotonic, and the capacity of chondrocyte volume regulation is weakened, leading to other pathological processes. The regulation of chondrocyte volume is jointly dominated by RVI and RVD, accompanied by the activation of a large number of ion channels and the transport of ions across the membrane.

Figure 5.

The internal and external circulation of osteoarthritis. Internal circulation: in chondrocytes, increased expression of aquaporin, chondrocyte volume control imbalance, mitochondrial damage, apoptosis, and inflammation are interrelated and interact to destroy chondrocytes. External circulation: the destruction of chondrocytes, the increase of cartilage matrix degradation, and the decrease of osmotic pressure of synovial fluid result in osteoarthritis.