Complex regulatory interactions at shape joint morphology and osteoarthritis disease risk.

Our ability to pinpoint causal variants using GWAS is dependent on understanding the dynamic epigenomic and epistatic context of each associated locus. Being the best studied skeletal locus, associates with many diseases and has a complex cis-regulatory architecture. We interrogate regulatory interactions and model disease variants and .

A novel methodology utilizing microchip implants to monitor individual activity and body temperature for assessing knee pain in group-housed rats.

The pain assessment in animals is challenging as they cannot verbally express the site and severity of pain. In this study, we tried a small implantable actimeter, "Nanotag", to monitor spontaneous locomotor activity and body temperature in animals suffering from a chemical-induced rat knee arthritis as compared to naïve and steroid-treated rats. Nanotag could detect the decrease in locomotor activity quickly after the arthritis induction and anti-inflammation analgesic treatment by intra-articular injection of steroid significantly improved locomotor activity.

PPARγ agonist treatment reduces fibroadipose tissue in secondary lymphedema by exhausting fibroadipogenic PDGFRα+ mesenchymal cells.

Secondary lymphedema occurs in up to 20% of patients after lymphadenectomy performed for the surgical management of tumors involving the breast, prostate, uterus, and skin. Patients develop progressive edema of the affected extremity due to retention of protein-rich lymphatic fluid. Despite compression therapy, patients progress to chronic lymphedema in which noncompressible fibrosis and adipose tissue are deposited within the extremity.

Temporomandibular Joint Fibrocartilage Contains CD105 Positive Mouse Mesenchymal Stem/Progenitor Cells with Increased Chondrogenic Potential.

Objective: A specific type of mesenchymal stem/progenitor cells (MSPCs), CD105 is reported to aid in cartilage regeneration through TGF-β/Smad2-signalling. The purpose of this study was to identify and characterize CD105 MSPCs in temporomandibular joint (TMJ) cartilage.

Materials And Methods: MSPCs were isolated from mouse TMJ condyle explants and evaluated for their clonogenicity and pluripotential abilities.

Chondrogenic differentiation of mouse CD105+ stem/progenitor cells on amino-group-functionalized biosilica-hydrogel scaffolds.

Objectives: Mesenchymal stem/progenitor cells (MSPCs) are critical for tissue regeneration. Moreover, the CD105 antigen identifies early MSPCs with increased chondrogenic differentiation ability. We hypothesized that amine-(NH)-functionalized biosilica incorporating hydrogel scaffolds, seeded with mCoSPCs would contribute to creating tissue-engineered scaffolds, capable of de novo cartilage synthesis.

Inflammatory cytokines and mechanical injury induce post-traumatic osteoarthritis-like changes in a human cartilage-bone-synovium microphysiological system.

Background: Traumatic knee injuries in humans trigger an immediate increase in synovial fluid levels of inflammatory cytokines that accompany impact damage to joint tissues. We developed a human in vitro cartilage-bone-synovium (CBS) coculture model to study the role of mechanical injury and inflammation in the initiation of post-traumatic osteoarthritis (PTOA)-like disease.

Methods: Osteochondral plugs (cartilage-bone, CB) along with joint capsule synovium explants (S) were harvested from 25 cadaveric distal femurs from 16 human donors (Collin's grade 0-2, 23-83years).

A FoxA2+ long-term stem cell population is necessary for growth plate cartilage regeneration after injury.

Longitudinal bone growth, achieved through endochondral ossification, is accomplished by a cartilaginous structure, the physis or growth plate, comprised of morphologically distinct zones related to chondrocyte function: resting, proliferating and hypertrophic zones. The resting zone is a stem cell-rich region that gives rise to the growth plate, and exhibits regenerative capabilities in response to injury. We discovered a FoxA2+group of long-term skeletal stem cells, situated at the top of resting zone, adjacent the secondary ossification center, distinct from the previously characterized PTHrP+ stem cells.

Overexpression of transcription factor FoxA2 in the developing skeleton causes an enlargement of the cartilage hypertrophic zone, but it does not trigger ectopic differentiation in immature chondrocytes.

We previously found that FoxA factors are necessary for chondrocyte differentiation. To investigate whether FoxA factors alone are sufficient to drive chondrocyte hypertrophy, we build a FoxA2 transgenic mouse in which FoxA2 cDNA is driven by a reiterated Tetracycline Response Element (TRE) and a minimal CMV promoter. This transgenic line was crossed with a col2CRE;Rosa26 mouse line to generate col2CRE;Rosa26;TgFoxA2 mice for inducible expression of FoxA2 in cartilage using doxycycline treatment.

Loss of Vlk in Prx1 Cells Delays the Initial Steps of Endochondral Bone Formation and Fracture Repair in the Limb.

Vertebrate lonesome kinase (Vlk) is a secreted tyrosine kinase important for normal skeletogenesis during embryonic development. Vlk null mice (Vlk ) are born with severe craniofacial and limb skeletal defects and die shortly after birth. We used a conditional deletion model to remove Vlk in limb bud mesenchyme (Vlk-Prx1 cKO) to assess the specific requirement for Vlk expression by skeletal progenitor cells during endochondral ossification, and an inducible global deletion model (Vlk-Ubq iKO) to address the role of Vlk during fracture repair.

The secreted tyrosine kinase VLK is essential for normal platelet activation and thrombus formation.

Tyrosine phosphorylation of extracellular proteins is observed in cell cultures and in vivo, but little is known about the functional roles of tyrosine phosphorylation of extracellular proteins. Vertebrate lonesome kinase (VLK) is a broadly expressed secretory pathway tyrosine kinase present in platelet α-granules. It is released from platelets upon activation and phosphorylates substrates extracellularly.

Joint disease-specificity at the regulatory base-pair level.

Given the pleiotropic nature of coding sequences and that many loci exhibit multiple disease associations, it is within non-coding sequence that disease-specificity likely exists. Here, we focus on joint disorders, finding among replicated loci, that GDF5 exhibits over twenty distinct associations, and we identify causal variants for two of its strongest associations, hip dysplasia and knee osteoarthritis. By mapping regulatory regions in joint chondrocytes, we pinpoint two variants (rs4911178; rs6060369), on the same risk haplotype, which reside in anatomical site-specific enhancers.

Enhancing the chondrogenic potential of chondrogenic progenitor cells by deleting RAB5C.

Osteoarthritis (OA) is the most prevalent chronic joint disease that affects a large proportion of the elderly population. Chondrogenic progenitor cells (CPCs) reside in late-stage OA cartilage tissue, producing a fibrocartilaginous extracellular matrix; these cells can be manipulated to deposit proteins of healthy articular cartilage. CPCs are under the control of SOX9 and RUNX2.

Endothelial cells produce angiocrine factors to regulate bone and cartilage via versatile mechanisms.

Blood vessels are conduits distributed throughout the body, supporting tissue growth and homeostasis by the transport of cells, oxygen and nutrients. Endothelial cells (ECs) form the linings of the blood vessels, and together with pericytes, are essential for organ development and tissue homeostasis through producing paracrine signalling molecules, called angiocrine factors. In the skeletal system, ECs - derived angiocrine factors, combined with bone cells-released angiogenic factors, orchestrate intercellular crosstalk of the bone microenvironment, and the coupling of angiogenesis-to-osteogenesis.

Evolutionary Selection and Constraint on Human Knee Chondrocyte Regulation Impacts Osteoarthritis Risk.

During human evolution, the knee adapted to the biomechanical demands of bipedalism by altering chondrocyte developmental programs. This adaptive process was likely not without deleterious consequences to health. Today, osteoarthritis occurs in 250 million people, with risk variants enriched in non-coding sequences near chondrocyte genes, loci that likely became optimized during knee evolution.

Molecular biology of meniscus pathology: Lessons learned from translational studies and mouse models.

Injury to any individual structure in the knee interrupts the overall function of the joint and initiates a cascade of biological and biomechanical changes whose endpoint is often osteoarthritis (OA). The knee meniscus is an integral component of knee biomechanics and may also contribute to the biological homeostasis of the joint. Meniscus injury altering knee function is associated with a high risk of OA progression, and may also be involved in the initiation of OA.

American Society for Bone and Mineral Research-Orthopaedic Research Society Joint Task Force Report on Cell-Based Therapies - Secondary Publication.

Cell-based therapies, defined here as the delivery of cells in vivo to treat disease, have recently gained increasing public attention as a potentially promising approach to restore structure and function to musculoskeletal tissues. Although cell-based therapy has the potential to improve the treatment of disorders of the musculoskeletal system, there is also the possibility of misuse and misrepresentation of the efficacy of such treatments. The medical literature contains anecdotal reports and research studies, along with web-based marketing and patient testimonials supporting cell-based therapy.

American Society for Bone and Mineral Research-Orthopaedic Research Society Joint Task Force Report on Cell-Based Therapies.

Cell-based therapies, defined here as the delivery of cells in vivo to treat disease, have recently gained increasing public attention as a potentially promising approach to restore structure and function to musculoskeletal tissues. Although cell-based therapy has the potential to improve the treatment of disorders of the musculoskeletal system, there is also the possibility of misuse and misrepresentation of the efficacy of such treatments. The medical literature contains anecdotal reports and research studies, along with web-based marketing and patient testimonials supporting cell-based therapy.

Chondromodulin-1 in health, osteoarthritis, cancer, and heart disease.

The human chondromodulin-1 (Chm-1, Chm-I, CNMD, or Lect1) gene encodes a 334 amino acid type II transmembrane glycoprotein protein with characteristics of a furin cleavage site and a putative glycosylation site. Chm-1 is expressed most predominantly in healthy and developing avascular cartilage, and healthy cardiac valves. Chm-1 plays a vital role during endochondral ossification by the regulation of angiogenesis.

Protein Cytl1: its role in chondrogenesis, cartilage homeostasis, and disease.

Cytokine-like protein 1 (Cytl1), also named Protein C17 or C4orf4 is located on human chromosome 4p15-p16 and encodes a polypeptide of 126 amino acid residues that displays characteristics of a secretory protein. Cytl1 is expressed by a sub-population of CD34 human mononuclear cells from bone marrow and cord blood, and by chondrocytes (cartilage-forming cells). In this review, we explore evidence suggesting that Cytl1 may be involved in the regulation of chondrogenesis, cartilage homeostasis and osteoarthritis progression, accompanied by the modulation of Sox9 and insulin-like growth factor 1 expression.

BMPs, TGFβ, and border security at the interzone.

Synovial joints enable movement and protect the integrity of the articular cartilage. Joints form within skeletal condensations destined to undergo chondrogenesis. The suppression of this chondrogenic program in the interzone is the first morphological sign of joint formation.

Reactivation of a developmental signaling center is required for therapeutic control of the murine periosteal niche.

Two decades after signals controlling bone length were discovered, the endogenous ligands determining bone width remain unknown. We show that postnatal establishment of normal bone width in mice, as mediated by bone-forming activity of the periosteum, requires BMP signaling at the innermost layer of the periosteal niche. This developmental signaling center becomes quiescent during adult life.