Purpose of review
This review focuses on the novel stress-induced and proinflammatory mechanisms underlying the pathogenesis of osteoarthritis, with particular attention to the role of synovitis and the contributions of other joint tissues to cellular events that lead to the onset and progression of the disease and irreversible cartilage damage.

Inflammation in osteoarthritis

Chondrogenesis occurs as a result of mesenchymal cell condensation and chondroprogenitor cell differentiation. Following chondrogenesis, the chondrocytes remain as resting cells to form the articular cartilage or undergo proliferation, terminal differentiation to chondrocyte hypertrophy, and apoptosis in a process termed endochondral ossification, whereby the hypertrophic cartilage is replaced by bone. Human adult articular cartilage is a complex tissue of matrix proteins that varies from superficial to deep layers and from loaded to unloaded zones. A major challenge to efforts to repair cartilage by stem cell-based and other tissue-engineering strategies is the inability of the resident chondrocytes to lay down a new matrix with the same properties as it had when it was formed during development. Thus, understanding and comparing the mechanisms of cartilage remodeling during development, osteoarthritis (OA), and aging may lead to more effective strategies for preventing cartilage damage and promoting repair. The pivotal proteinase that marks OA progression is matrix metalloproteinase 13 (MMP-13), the major type II collagen-degrading collagenase, which is regulated by both stress and inflammatory signals. We and other investigators have found that there are common mediators of these processes in human OA cartilage. We also observe temporal and spatial expression of these mediators in early through late stages of OA in mouse models and are analyzing the consequences of knockout or transgenic overexpression of critical genes. Since the chondrocytes in adult human cartilage are normally quiescent and maintain the matrix in a low turnover state, understanding how they undergo phenotypic modulation and promote matrix destruction and abnormal repair in OA may to lead to identification of critical targets for therapy to block cartilage damage and promote effective cartilage repair.

https://journals.sagepub.com/doi/pdf/10.1177/1759720X12448454

Chondrogenesis, chondrocyte differentiation, and articular cartilage metabolism in health and osteoarthritis.

https://cyberleninka.org/article/n/130052.pdf

Hereditary spastic paraplegia: Clinical-genetic characteristics and evolving molecular mechanisms

Osteoarthritis (OA) is a whole joint disease, in which thinning and disappearance of cartilage is a critical determinant in OA progression. The rupture of cartilage homeostasis whatever its cause (aging, genetic predisposition, trauma or metabolic disorder) induces profound phenotypic modifications of chondrocytes, which then promote the synthesis of a subset of factors that induce cartilage damage and target other joint tissues. Interestingly, among these factors are numerous components of the inflammatory pathways. Chondrocytes produce cytokines, chemokines, alarmins, prostanoids, and adipokines and express numerous cell surface receptors for cytokines and chemokines, as well as Toll-like receptors. These receptors activate intracellular signaling pathways involved in inflammatory and stress responses of chondrocytes in OA joints. This review focuses on mechanisms responsible for the maintenance of cartilage homeostasis and highlights the role of inflammatory processes in OA progression.

/pdf/homeostatic-mechanisms-in-articular-cartilage-and-role-of-43038pcya8.pdf

Homeostatic mechanisms in articular cartilage and role of inflammation in osteoarthritis

Aims : Phytosterols are a subgroup of the steroids, as an important class of bioorganic molecules,widespread in plants, animals, marines as well as fungi and have similarity to cholesterol in structure. These compounds have a long history of consumption as food or pharmaceutical products, and generally recognized as safe without undesirable side effects.

The Story of Beta-sitosterol-A Review

https://www.oarsijournal.com/article/S1063-4584(09)00217-9/pdf

Stigmasterol: a phytosterol with potential anti-osteoarthritic properties

Thirty-four different loci for hereditary spastic paraplegias have been mapped, and 16 responsible genes have been identified. Autosomal recessive forms of spastic paraplegias usually have clinically complex phenotypes but the SPG5, SPG24 and SPG28 loci are considered to be associated with 'pure' forms of the disease. Very recently, five mutations in the CYP7B1 gene, encoding a cytochrome P450 oxysterol 7-alpha hydroxylase and expressed in brain and liver, have been found in SPG5 families. We analysed the coding region and exon-intron boundaries of the CYP7B1 gene by direct sequencing in a series of 82 unrelated autosomal recessive hereditary spastic paraplegia index patients, manifesting either a pure (n = 52) or a complex form (n = 30) of the disease, and in 90 unrelated index patients with sporadic pure hereditary spastic paraplegia. We identified eight, including six novel, mutations in CYP7B1 segregating in nine families. Three of these mutations were nonsense (p.R63X, p.R112X, p.Y275X) and five were missense mutations (p.T297A, p.R417H, p.R417C, p.F470I, p.R486C), the last four clustering in exon 6 at the C-terminal end of the protein. Residue R417 appeared as a mutational hot-spot. The mean age at onset in 16 patients was 16.4 +/- 12.1 years (range 4-47 years). After a mean disease duration of 28.3 +/- 13.4 years (10-58), spasticity and functional handicap were moderate to severe in all cases. Interestingly, hereditary spastic paraplegia was pure in seven SPG5 families but complex in two. In addition, white matter hyperintensities were observed on brain magnetic resonance imaging in three patients issued from two of the seven pure families. Lastly, the index case of one family had a chronic autoimmune hepatitis while his eldest brother died from cirrhosis and liver failure. Whether this association is fortuitous remains unsolved, however. The frequency of CYP7B1 mutations were 7.3% (n = 6/82) in our series of autosomal recessive hereditary spastic paraplegia families and 3.3% (n = 3/90) in our series of sporadic pure spastic paraplegia. The recent identification of CYP7B1 as the gene responsible for SPG5 highlights a novel molecular mechanism involved in hereditary spastic paraplegia determinism.

/pdf/cyp7b1-mutations-in-pure-and-complex-forms-of-hereditary-15xrtul5ra.pdf

Françoise Chevy

Papers

Stigmasterol: a phytosterol with potential anti-osteoarthritic properties

CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5.

153 anti-inflammatory properties of stigmasterol in cartilage: new insights