Primary Cilia Direct Murine Articular Cartilage Tidemark Patterning Through Hedgehog Signaling and Ambulatory Load

Abstract

Articular cartilage (AC) is essential for body movement but is highly susceptible to degenerative diseases and has poor self-repair capacity. To improve current subpar regenerative treatments, developmental mechanisms of AC should be clarified and, specifically, how its postnatal multizone organization is acquired. Primary cilia are cell surface organelles crucial for mammalian tissue morphogenesis. Although their importance for chondrocyte function is appreciated, their specific roles in postnatal AC morphogenesis remain unclear. To explore these mechanisms, we used a murine conditional loss-of-function approach (Ift88-flox) targeting jointlineage progenitors (Gdf5Cre) and monitored postnatal knee AC development. Joint formation and growth up to juvenile stages were largely unaffected. However, mature AC (aged 2 months) exhibited disorganized extracellular matrix, decreased aggrecan and collagen II due to reduced gene expression (not increased catabolism), and marked reduction of AC modulus by 30%-50%. In addition, and unexpectedly, we discovered that tidemark patterning was severely disrupted, as was hedgehog signaling, and exhibited specificity based on regional load-bearing functions of AC. Interestingly, Prg4 expression was markedly increased in highly loaded sites in mutants. Together, our data provide evidence that primary cilia orchestrate postnatal AC morphogenesis including tidemark topography, zonal matrix composition, and ambulation load responses.

Structural Characterization Analyses of Low Brass Filler Biomaterial for Hard Tissue Implanted Scaffold Applications

“…There is a necessity to create a biomaterial [1] for hard tissue [2] implanted scaffold applications [3] to reduce the global burden of bone disease and fractures [4]. These implanted scaffolds are translational therapeutic approaches [5] using tissue engineering techniques [6] to treat degenerative diseases [7] and improve cartilage regeneration efficiency [8] for osteoarthritis patients. At present, titanium filler [9] is still the most commonly used in metallic scaffolds [10] in advanced combinations with polymer-based biomaterials [11][12][13] during the green composite fabrication processes [14].…”

The factory, the antenna and the scaffold: the three-way interplay between the Golgi, cilium and extracellular matrix underlying tissue function

“…Similarly, loss of ciliary resident protein polycystin-1 impedes osteoblast differentiation ( Xiao et al, 2006 ) and collagen production ( Mangos et al, 2010 ). In cartilage, loss of IFT disrupts Hh and Wnt signalling, preventing chondrocyte differentiation in the growth plate ( Wang et al, 2013 ) and impacting articular cartilage thickness and tidemark patterning (calcification) in post-natal joints ( Rux et al, 2022 ; Coveney et al, 2022 ). The Evc protein, mutated in the skeletal ciliopathy Ellis van-Crevald syndrome, has also been shown to mediate Ihh signalling in both chondrocytes and osteoblasts to promote growth plate development ( Pacheco et al, 2012 ; Ruiz-Perez et al, 2007 ).…”

Role of the hedgehog signaling pathway in rheumatic diseases: An overview

“…Thus, there may be other factors other than IL-1β involved in the degradation of OA ECM by Hh. Primary cilia are involved in the development and maintenance of articular cartilage and regulated Hh signaling ( 43 ). Depletion of primary cilia in articular chondrocytes activates Hh signaling, resulting in symptoms of early OA with a reduced ratio of Gli3 repressor to activator ( 44 ).…”