Absence of collagen IX accelerates hypertrophic differentiation in the embryonic mouse spine through a disturbance of the Ihh-PTHrP feedback loop

Abstract

Collagen IX (Col IX) is a component of the cartilage extracellular matrix and contributes to its structural integrity. Polymorphisms in the genes encoding the Col IX ɑ2- and ɑ3-chains are associated with early onset of disc degeneration. Col IX-deficient mice already display changes in the spine at the newborn stage and premature disc degeneration starting at 6 months of age. To determine the role of Col IX in early spine development and to identify molecular mechanisms underlying disc degeneration, the embryonic development of the spine was analyzed in Col IX -/- mice. Histological staining was used to show tissue morphology at different time points. Localization of extracellular matrix proteins as well as components of signaling pathways were analyzed by immunohistochemistry. Developing vertebral bodies of Col IX -/- mice were smaller and already appeared more compact at E12.5. At E15.5, vertebral bodies of Col IX -/- mice revealed an increased number of hypertrophic chondrocytes as well as enhanced staining for the terminal differentiation markers alkaline phosphatase and collagen X. This correlates with an imbalance in the Ihh-PTHrP signaling pathway at this time point, reflected by an increase of Ihh and a concomitant decrease of PTHrP expression. An accelerated hypertrophic differentiation caused by a disturbed Ihh-PTHrP signaling pathway may lead to a higher bone mineral density in the vertebral bodies of newborn Col IX -/- mice and, as a result, to the early onset of disc degeneration.

Inhibition of Ihh Reverses Temporomandibular Joint Osteoarthritis via a PTH1R Signaling Dependent Mechanism

“…Osteoarthritis (OA) is a type of joint problem, which is often caused by biomechanical factors, and cartilage is the most frequently involved site [1]. Cells located in articular cartilage are differentiated from early to late stage [2]. The superficial zone cells are proliferative, and the deep zone chondrocytes are hypertrophic, from which stage the cells undergo terminal differentiation [3].…”

Primary Cilia: A Cellular Regulator of Articular Cartilage Degeneration

“…The Ihh is secreted by prehypertrophic chondrocytes to regulate hypertrophy and mineralization of chondrocytes during chondrogenesis [73]. Instead, parathyroid hormone-related protein (PTHrP) can inhibit chondrocyte hypertrophy and maintain chondrocyte proliferation [74,75]. Multiple studies have demonstrated that increased Ihh signaling activates the PTHrP signaling pathway in hypertrophic chondrocytes, causing overexpression of genes associated with cartilage degeneration and the development of OA [76][77][78].…”

The Matrilin-3 T298M mutation predisposes for post-traumatic osteoarthritis in a knock-in mouse model

“…Visualization of proteoglycans and immunohistochemical staining to detect matrilin-1 (rabbit polyclonal, 1:1000) 27 , matrilin-3 (rabbit polyclonal, 1:1000) 3 and aggrecan (Merck, rabbit polyclonal, 1:100) was performed as described 28 . The 3-amino-9-ethylcarbazole (AEC) substrate-chromogen kit (DAKO) was used for a more sensitive detection.…”