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Altered paracrine signaling from the injured knee joint impairs postnatal long bone growth.

ABSTRACT: Regulation of organ growth is a poorly understood process. In the long bones, the growth plates (GPs) drive elongation by generating a scaffold progressively replaced by bone. Although studies have focused on intrinsic GP regulation, classic and recent experiments suggest that local signals also modulate GP function. We devised a genetic mouse model to study extrinsic long bone growth modulation, in which injury is specifically induced in the left hindlimb, such that the right hindlimb serves as an internal control. Remarkably, when only mesenchyme cells surrounding postnatal GPs were killed, left bone growth was nevertheless reduced. GP signaling was impaired by altered paracrine signals from the knee joint, including activation of the injury response and, in neonates, dampened IGF1 production. Importantly, only the combined prevention of both responses rescued neonatal growth. Thus, we identified signals from the knee joint that modulate bone growth and could underlie establishment of body proportions.

SUBMITTER: Rosello-Diez A

PROVIDER: S-EPMC5526667 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Altered paracrine signaling from the injured knee joint impairs postnatal long bone growth.

Roselló-Díez Alberto A Stephen Daniel D Joyner Alexandra L AL

eLife 20170725

Regulation of organ growth is a poorly understood process. In the long bones, the growth plates (GPs) drive elongation by generating a scaffold progressively replaced by bone. Although studies have focused on intrinsic GP regulation, classic and recent experiments suggest that local signals also modulate GP function. We devised a genetic mouse model to study extrinsic long bone growth modulation, in which injury is specifically induced in the left hindlimb, such that the right hindlimb serves as ...[more]

PMID: 28741471

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Project description:BACKGROUND:Osteoclasts have been strongly implicated in osteoarthritic cartilage degradation, at least indirectly via bone resorption, and have been shown to degrade cartilage in vitro. The osteoclast resorption processes required to degrade subchondral bone and cartilage-the remodeling of which is important in the osteoarthritic disease process-have not been previously described, although cathepsin K has been indicated to participate. In this study we profile osteoclast-mediated degradation of bovine knee joint compartments in a novel in vitro model using biomarkers of extracellular matrix (ECM) degradation to assess the potential of osteoclast-derived resorption processes to degrade different knee joint compartments. METHODS:Mature human osteoclasts were cultured on ECMs isolated from bovine knees-articular cartilage, cortical bone, and osteochondral junction ECM (a subchondral bone-calcified cartilage mixture)-in the presence of inhibitors: the cystein protease inhibitor E-64, the matrix metalloproteinase (MMP) inhibitor GM6001, or the vacuolar-type H+-ATPase (V-ATPase) inhibitor diphyllin. Biomarkers of bone (calcium and C-terminal type I collagen (CTX-I)) and cartilage (C2M) degradation were measured in the culture supernatants. Cultures without osteoclasts were used as background samples. Background-subtracted biomarker levels were normalized to the vehicle condition and were analyzed using analysis of variance with Tukey or Dunnett's T3 post hoc test, as applicable. RESULTS:Osteochondral CTX-I release was inhibited by E-64 (19% of vehicle, p = 0.0008), GM6001 (51% of vehicle, p = 0.013), and E-64/GM6001 combined (4% of vehicle, p = 0.0007)-similarly to bone CTX-I release. Diphyllin also inhibited osteochondral CTX-I release (48% of vehicle, p = 0.014), albeit less than on bone (4% of vehicle, p < 0.0001). Osteochondral C2M release was only inhibited by E-64 (49% of vehicle, p = 0.07) and GM6001 (14% of vehicle, p = 0.006), with complete abrogation when combined (0% of vehicle, p = 0.004). Cartilage C2M release was non-significantly inhibited by E-64 (69% of vehicle, p = 0.98) and was completely abrogated by GM6001 (0% of vehicle, p = 0.16). CONCLUSIONS:Our study supports that osteoclasts can resorb non-calcified and calcified cartilage independently of acidification. We demonstrated both MMP-mediated and cysteine protease-mediated resorption of calcified cartilage. Osteoclast functionality was highly dependent on the resorbed substrate, as different ECMs required different osteoclast processes for degradation. Our novel culture system has potential to facilitate drug and biomarker development aimed at rheumatic diseases, e.g. osteoarthritis, where pathological osteoclast processes in specific joint compartments may contribute to the disease process.

Project description:BackgroundBone marrow edema (BME) is a radiological term which can be found in many conditions with varied pathogenesis and histopathological images. It usually presents with pain in the affected joint and is diagnosed with MRI. Subchondroplasty (SCP) and core decompression (CD) are the surgical methods that are available to achieve pain relief and functional improvement. Both surgical methods have their own indications and are used depending on the patient's history. The aim of this literature review article is to discuss the surgical modalities for the management of bone marrow edema focusing on the knee joint. Such topic which analyzes both surgical methods for treatment of bone marrow edema of the knee joint has never been described in a review article before.Materials and methodsFor the purpose of our manuscript we thoroughly searched electronic databases such as Pubmed and Medline to acquire the appropriate material for our review paper. Only English articles were used in this review. In our study we included every article that had described the surgical management of BME of the knee by CD and SCP. In the discussion we included 18 studies (9 CD and 9 SCP) with a total number of patients equal to 397, while 206/397 had undergone surgical intervention (169 underwent SCP and 37 CD).ResultsFollow-up of 180 patients out of 206 were available for our review. A total number of 166 patients (92.2%) were successfully treated. Specifically, 29 (100%) patients were treated by CD and 137 (90.7%) by SCP. In a study, 10 patients who underwent SCP for BME secondary to advanced osteoarthritis (OA) yielded poor results. In other studies, pain persistency was observed in 2 patients, 1 patient had postoperative infection and another patient eventually underwent total knee arthroplasty (TKA). 70% prevention of TKA was achieved by SCP in a study of 66 patients with BME secondary to advanced OA. Thus, a total number of 166 patients were considered as clinical success and 14 patients as clinical failure.ConclusionsThe included studies that have been published referred to the surgical methods of CD or SCP for the management of BME of the knee but none of that summarizes all current studies on both methods. Those studies seem that CD is a surgical technique that is proposed to perform in patients without findings of OA that usually fail to respond to conservative treatment. On the other hand, the option of SCP technique is carried out in patients with varied stage of OA associated with subchondral BME. Both methods aim to reduce the pain and to improve function in the setting of subchondral BME. Nevertheless it is not clear in literature which method is the best according to the criteria of the use. This literature review shows a lack of standardized guidelines with respect to diagnosis and surgical treatment.

Dataset Information

Altered paracrine signaling from the injured knee joint impairs postnatal long bone growth.

Publications

Altered paracrine signaling from the injured knee joint impairs postnatal long bone growth.

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