Angiogenesis and inflammation are closely integrated processes in osteoarthritis (OA) and may affect disease progression and pain. Inflammation can stimulate angiogenesis, and angiogenesis can facilitate inflammation. Angiogenesis can also promote chondrocyte hypertrophy and endochondral ossification, contributing to radiographic changes in the joint. Inflammation sensitizes nerves, leading to increased pain. Innervation can also accompany vascularization of the articular cartilage, where compressive forces and hypoxia may stimulate these new nerves, causing pain even after inflammation has subsided. Inhibition of inflammation and angiogenesis may provide effective therapeutics for the treatment of OA by improving symptoms and retarding joint damage. This review aims to summarize (i) the evidence that angiogenesis and inflammation play an important role in the pathophysiology of OA and (ii) possible directions for future research into therapeutics that could effectively treat this disease.

Osteoarthritis, angiogenesis and inflammation

Cbfa1, a transcription factor that belongs to the runt-domain gene family, plays an essential role in osteogenesis. Cbfa1-deficient mice completely lacked both intramembranous and endochondral ossification, owing to the maturational arrest of osteoblasts, indicating that Cbfa1 has a fundamental role in osteoblast differentiation. However, Cbfa1 was also expressed in chondrocytes, and its expression was increased according to the maturation of chondrocytes. Terminal hypertrophic chondrocytes expressed Cbfa1 extensively. The significant expression of Cbfa1 in hypertrophic chondrocytes was first detected at embryonic day 13.5 (E13.5), and its expression in hypertrophic chondrocytes was most prominent at E14.5-16.5. In Cbfa1-deficient mice, whose entire skeleton was composed of cartilage, the chondrocyte differentiation was disturbed. Calcification of cartilage occurred in the restricted parts of skeletons, including tibia, fibula, radius, and ulna. Type X collagen, BMP6, and Indian hedgehog were expressed in their hypertrophic chondrocytes. However, osteopontin, bone sialoprotein, and collagenase 3 were not expressed at all, indicating that they are directly regulated by Cbfa1 in the terminal hypertrophic chondrocytes. Chondrocyte differentiation was severely disturbed in the rest of the skeleton. The expression of PTH/PTHrP receptor, Indian hedgehog, type X collagen, and BMP6 was not detected in humerus and femur, indicating that chondrocyte differentiation was blocked before prehypertrophic chondrocytes. These findings demonstrate that Cbfa1 is an important factor for chondrocyte differentiation.

https://anatomypubs.onlinelibrary.wiley.com/doi/pdf/10.1002/%28SICI%291097-0177%28199904%29214%3A4%3C279%3A%3AAID-AJA1%3E3.0.CO%3B2-W

Maturational disturbance of chondrocytes in Cbfa1-deficient mice.

The growth plate is the final target organ for longitudinal growth and results from chondrocyte proliferation and differentiation. During the first year of life, longitudinal growth rates are high, followed by a decade of modest longitudinal growth. The age at onset of puberty and the growth rate during the pubertal growth spurt (which occurs under the influence of estrogens and GH) contribute to sex difference in final height between boys and girls. At the end of puberty, growth plates fuse, thereby ceasing longitudinal growth. It has been recognized that receptors for many hormones such as estrogen, GH, and glucocorticoids are present in or on growth plate chondrocytes, suggesting that these hormones may influence processes in the growth plate directly. Moreover, many growth factors, i.e., IGF-I, Indian hedgehog, PTHrP, fibroblast growth factors, bone morphogenetic proteins, and vascular endothelial growth factor, are now considered as crucial regulators of chondrocyte proliferation and differentiation. In this review, we present an update on the present perception of growth plate function and the regulation of chondrocyte proliferation and differentiation by systemic and local regulators of which most are now related to human growth disorders.

/pdf/systemic-and-local-regulation-of-the-growth-plate-1vvm4bgnzn.pdf

Systemic and Local Regulation of the Growth Plate

Chondrocytes play critical roles at several stages of endochondral ossification. At the onset of skeletal development, in the areas of the skeleton that will undergo endochondral ossification, undifferentiated mesenchymal cells form condensations that have the shape of the future skeletal elements. Cells within these mesenchymal condensations differentiate into chondrocytes that express specific molecular markers, such as α1(II) collagen, whereas the remaining undifferentiated mesenchymal cells at the periphery of the condensations form the perichondrium (for review, see ref. 1). Once these cartilaginous models have formed, chondrocytes in their centers further differentiate into hypertrophic chondrocytes. At the time chondrocyte hypertrophy occurs, the perichondrial cells differentiate into osteoblasts to form, around the cartilaginous core, the bone collar (2).

/pdf/continuous-expression-of-cbfa1-in-nonhypertrophic-8nlyz42aza.pdf

Continuous expression of Cbfa1 in nonhypertrophic chondrocytes uncovers its ability to induce hypertrophic chondrocyte differentiation and partially rescues Cbfa1-deficient mice

Scleraxis positively regulates the expression of tenomodulin, a differentiation marker of tenocytes

Identification of Chondromodulin I as a Novel Endothelial Cell Growth Inhibitor PURIFICATION AND ITS LOCALIZATION IN THE AVASCULAR ZONE OF EPIPHYSEAL CARTILAGE

A novel chondromodulin-II protein having a molecular weight of about 16,000 dalton on SDS-PAGE, capable of stimulating the growth of chondrocytes with or without fibroblast growth factor and promoting the differential potency of said cells, and a pharmaceutical composition containing said protein as an active ingredient.

Akihito Kamizono

Papers

Identification of Chondromodulin I as a Novel Endothelial Cell Growth Inhibitor PURIFICATION AND ITS LOCALIZATION IN THE AVASCULAR ZONE OF EPIPHYSEAL CARTILAGE

Chondromodulin-II protein