Osteoarthritis-Like Changes in Bardet–Biedl Syndrome Mutant Ciliopathy Mice (Bbs1M390R/M390R): Evidence for a Role of Primary Cilia in Cartilage Homeostasis and Regulation of Inflammation

Abstract

Osteoarthritis (OA) is a debilitating inflammation related disease characterized by joint pain and effusion, loss of mobility, and deformity that may result in functional joint failure and significant impact on quality of life. Once thought of as a simple “wear and tear” disease, it is now widely recognized that OA has a considerable metabolic component and is related to chronic inflammation. Defects associated with primary cilia have been shown to be cause OA-like changes in Bardet–Biedl mice. We examined the role of dysfunctional primary cilia in OA in mice through the regulation of the previously identified degradative and pro-inflammatory molecular pathways common to OA. We observed an increase in the presence of pro-inflammatory markers TGFβ-1 and HTRA1 as well as cartilage destructive protease MMP-13 but a decrease in DDR-2. We observed a morphological difference in cartilage thickness in Bbs1M390R/M390R mice compared to wild type (WT). We did not observe any difference in OARSI or Mankin scores between WT and Bbs1M390R/M390R mice. Primary cilia appear to be involved in the upregulation of biomarkers, including pro-inflammatory markers common to OA.

Regulation of the Extracellular Matrix by Ciliary Machinery

“…Knockout of the BBS proteins BBS2 or BBS6, or mutation of BBS1, resulted in complete loss of superficial articular cartilage and reduced proteoglycan content in the remaining cartilage. In contrast, analysis of the BBS1 mutant at earlier time points showed that mutant mice have thicker cartilage relative to WT, but also have areas of articular surface erosion [84]. Similarly, cartilage-specific deletion of IFT88 resulted in increased cartilage thickness and staining for type II collagen and proteoglycans, but also upregulation of Adamts5, Mmp13 and Runx2 expression, and Hh signalling [85].…”

Topical Application of Wogonin Provides a Novel Treatment of Knee Osteoarthritis

“…The subsequent decalcification procedure and embedding in paraffin wax were done according to the procedure reported (Siebert et al, 2015). Knees were sectioned at 6 µM thickness using a Heidelberg Microm microtome and the corresponding sections of tissue were stained with Safranin-O and Fast Green as previously described for histological analysis (Sheffield et al, 2018). Using a light microscope equipped with a digital camera, photographs of the stained joint tissue were taken at 10 and 20X magnification.…”

Physiological and Pathophysiological Aspects of Primary Cilia—A Literature Review with View on Functional and Structural Relationships in Cartilage

“…In this context, increased matrix metalloproteinase 13 (MMP-13) levels play a critical role in the pathophysiology of OA [99]. MMP-13 cleaves collagen II and leads to a degradation of the ECM [100]. Several pathways are known to activate MMP-13 gene expression ( Figure 6).…”

“…Several pathways are known to activate MMP-13 gene expression ( Figure 6). On the one hand, inflammatory signals in form of IL-1β in interaction with stress inducible nuclear protein 1 (NUPR1) leads to an increased expression of MMP-13 [100]. In this context, Wann et al demonstrated that the ciliary length was increased through a treatment with IL-1β in human chondrocytes via Proteinkinase A (PKA) and suggest a link between inflammation and PC in OA [101].…”