The pericellular matrix (PCM) is a specialized, narrow matrix surrounding each chondrocyte in articular cartilage, together constituting the chondron - the fundamental metabolic and functional unit of cartilage. The PCM plays a vital role in mediating biomechanical and biochemical signals essential for chondrocyte function. In osteoarthritis (OA), a chronic joint disorder characterized by progressive cartilage degradation, the PCM is one of the earliest sites of catabolic degradation, primarily driven by matrix metalloproteinases (MMPs). This study aims to investigate the functional relationship between PCM degradation and chondrocyte mechanosignaling, with an emphasis on MMP-driven changes in mechanotransduction in osteoarthritic cartilage. Human chondrons (N = 64) were incubated with MMP-2, MMP-3, and MMP-7, and structural changes were assessed histologically by evaluating perlecan and collagen type VI. Cellular elasticity was measured using atomic force microscopy (AFM), and mechanically evoked intracellular Ca2+ transients were assessed via AFM single-cell indentations (500 nN). All three MMPs induced pronounced catabolic effects on the PCM structure, showing distinct impacts on collagen type VI and perlecan, as well as on the biomechanical properties (p < 0.001). MMP-driven alterations in PCM integrity significantly reduced the Ca2+ transients of chondrons in response to mechanical stimuli (p < 0.001). While TRPV4 activation was elevated in intact chondrons, PIEZO channels were involved in mechanotransduction in both healthy and MMP-treated chondrons. In osteoarthritic stages, the mechanotransduction dynamics shifted significantly towards PIEZO channels. This study elucidates the interplay between MMP-mediated PCM degradation, structural-functional dynamics, and chondrocyte mechanotransduction, underscoring the critical role of the PCM in maintaining normal chondrocyte functionality and mechanosensing. STATEMENT OF SIGNIFICANCE: Osteoarthritis (OA) is a prevalent degenerative joint disease affecting millions worldwide. Central to its pathology is the degradation of the pericellular matrix (PCM) by matrix metalloproteinases (MMPs), which disrupts chondrocyte mechanotransduction, altering cellular responses to mechanical stimuli. This study explores the impact of MMP-2, MMP-3, and MMP-7 on PCM structure and chondrocyte mechanosensing. Our results reveal that MMP-induced degradation significantly compromises PCM structural integrity, leading to altered mechanotransduction dynamics in chondrocytes. Degradation specifically redirects the primary function of ion channels from TRPV4 to PIEZO channels in cells impacted by MMPs. This highlights the interplay between MMP-mediated PCM degradation, chondrocyte mechanotransduction and as thus structural-functional dynamics, underscoring the critical role of the PCM in maintaining normal chondrocyte functionality and mechanosensing.

Bone is a highly mechanosensitive tissue, where mechanical signaling plays a central role in maintaining skeletal homeostasis. Mechanotransduction regulates the balance between bone formation and resorption through coordinated interactions among bone cells. Key mechanosensing structures—including the extracellular/pericellular matrix (ECM/PCM), integrins, ion channels, connexins, and primary cilia, translate mechanical cues into biochemical signals that drive bone adaptation. Disruptions in mechanotransduction are increasingly recognized as an important factor in osteoporosis. Under pathological conditions, impaired mechanical signaling reduces bone formation and accelerates bone resorption, leading to skeletal fragility. Defects in mechanotransduction disrupt key pathways involved in bone metabolism, further exacerbating bone loss. Therefore, targeting mechanotransduction presents a promising pharmacological strategy for osteoporosis treatment. Recent advances have focused on developing drugs that enhance bone mechanosensitivity by modulating key mechanotransduction pathways, including integrins, ion channels, connexins, and Wnt signaling. A deeper understanding of mechanosignaling mechanisms may pave the way for novel therapeutic approaches aimed at restoring bone mass, mechanical integrity, and mechanosensitive bone adaptation.

The pericellular matrix (PCM) serves a critical role in signal transduction and mechanoprotection in chondrocytes. Osteoarthritis (OA) leads to a gradual deterioration of the cartilage, marked by a shift in the spatial arrangement of chondrocytes from initially isolated strands to large cell clusters in end-stage degeneration. These changes coincide with progressive enzymatic breakdown of the PCM. This study aims to assess the role and involvement of specific matrix metalloproteinases (MMPs) in PCM degradation during OA. We selected cartilage samples from 148 OA patients based on the predominant spatial chondrocyte patterns. The presence of various MMPs (-1,-2,-3,-7,-8,-9,-10,-12,-13) was identified by multiplexed immunoassays. For each pattern and identified MMP, the levels and activation states (pro-form vs. active form) were measured by zymograms and western blots. The localization of these MMPs was determined using immunohistochemical labeling. To verify these results, healthy cartilage was exposed to purified MMPs, and the consecutive structural integrity of the PCM was analyzed through immunolabeling and proximity ligation assay. Screening showed elevated levels of MMP-1,-2,-3,-7, and -13, with their expression profile showing a clear dependency of the degeneration stage. MMP-2 and -7 were localized in the PCM, whereas MMP-1,-7, and -13 were predominantly intracellular. We found that MMP-2 and -3 directly disrupt collagen type VI, and MMP-3 and -7 destroy perlecan. MMP-2, -3, and -7 emerge as central players in early PCM degradation in OA. With the disease's initial stages already displaying elevated peaks in MMP expression, this insight may guide early targeted therapies to halt abnormal PCM remodeling. Statement of significance: Osteoarthritis (OA) causes a gradual deterioration of the articular cartilage, accompanied by a progressive breakdown of the pericellular matrix (PCM). The PCM's crucial function in protecting and transmitting signals within chondrocytes is impaired in OA. By studying 148 OA-patient cartilage samples, the involvement of matrix metalloproteinases (MMPs) in PCM breakdown was explored. Findings highlighted elevated levels of certain MMPs linked to different stages of degeneration. Notably, MMP-2, -3, and -7 were identified as potent contributors to early PCM degradation, disrupting key components like collagen type VI and perlecan. Understanding these MMPs' roles in initiating OA progression, especially in its early stages, provides insights into potential targets for interventions to preserve PCM integrity and potentially impeding OA advancement.