Inverse relationship between matrix remodeling and lipid metabolism during osteoarthritis progression in the STR/ORT mouse

Abstract

Objective. The biologic changes associated with osteoarthritis (OA) are incompletely understood. The aim of this study was to elucidate the molecular mechanisms underlying OA progression in an STR/Ort murine model of spontaneous disease.Methods. Global patterns of gene expression were assessed using microarray analysis of articular cartilage/subchondral bone from the tibial plateaus of STR/Ort mice at 3, 9, and 12 months of age. The age-dependent severity of osteophyte formation and extent of cartilage damage were determined in the corresponding femurs using microfocal computed tomography and the Mankin histologic scoring system. Pathway analysis was used to identify the functions of genes associated with OA progression, and changes in gene expression were confirmed using immunohistochemistry.Results. Six hundred twenty-one genes were associated with both osteophyte formation and cartilage damage in the STR/Ort joints. Genes involved in the development/function of connective tissue and in lipid metabolism were most significantly enriched and regulated during disease progression. Genes directly interacting with peroxisome proliferator-activated receptor ␣ (PPAR␣)/PPAR␥ were down-regulated, whereas those genes involved with connective tissue remodeling were up-regulated during disease progression. Associations of down-regulation of myotubularinrelated phosphatase 1 (a phosphoinositide 3-phosphatase involved in lipid signaling) and up-regulation of biglycan (a member of the small leucine-rich protein family known to modulate osteoblast differentiation and matrix mineralization) with OA progression were confirmed by immunohistochemistry.Conclusion. Since adipogenesis and osteogenesis are inversely related in the developing skeletal tissue, these results suggest that a shift in the differentiation of mesenchymal cells from adipogenesis toward osteogenesis is a component of the OA pathophysiologic processes occurring in the tibial plateau joints of STR/Ort mice.

Aqueous Fraction of Huogu Formula Promotes Osteogenic Differentiation of Bone Marrow Stromal Cells Through the BMP and Wnt Signaling Pathways

“…6,9 There is an inverse relationship between osteogenesis and adipogenesis; typically, increased osteogenesis is associated with decreased adipogenesis. [23][24][25] Furthermore, quite a number studies have manifested that transplanted autologous or allogeneic MSCs were capable of survival, proliferation, and differentiation into osteoblasts directly in the necrotic femoral head on humans 26-28 and a variety of animal models; for example, in mouse, 29 rabbit, 30,31 dog, 32 and sheep. 33 Thus, regulation on the osteogenesis and adipogenesis of MSCs is the novel therapeutics for ONFH treatment.…”

Differential Age-Related Bone Architecture Changes between Female and Male STR/Ort Mice

“…Acceleration of osteoclastogenesis by ovariectomy significantly increased the bone marrow space, even when ovariectomy was performed at 15 weeks of age, at which time the bone marrow space had nearly entirely disappeared. Recently, peroxisome proliferatoractivated receptor-g (PPAR-g) signaling, which plays an important role for pro-osteoclastogenic differentiation [29], was shown to be downregulated in male STR/Ort mice [30]. Tie2Cre-mediated hematopoietic cell-specific PPAR-g deletion leads to osteopetrosis, which is characterized by markedly increased bone volume and a reduced medullary cavity space in Tb.th and Tb.N.…”

Hyperlipidemia and Hyperinsulinemia in the Spontaneous Osteoarthritis Mouse Model, STR/Ort

“…However, relationships between hyperlipidemic conditions and lipotoxicity have not been investigated in organs other than bone [31]. It is not known whether any of these toxic responses influence the underlying mechanism and/or progression of primary osteoarthritis.…”