Agent containing boron compounds for the prevention and treatment of tibial dyschondroplasia

Abstract

The invention relates to an agent containing boron compounds, including boric acid (BA) and sodium pentaborate pentahydrate (SPP), which exhibit low toxicity and high bioavailability and provide a more effective, safe, and targeted solution for the prevention and treatment of tibial dyschondroplasia (TD), a metabolic skeletal disorder commonly observed in broiler chickens.

Description

[0001] DESCRIPTION

[0002] AGENT CONTAINING BORON COMPOUNDS FOR THE PREVENTION AND TREATMENT OF TIBIAL DYSCHONDROPLASIA

[0003] TECHNICAL FIELD

[0004] The present invention relates to an agent containing boron compounds, specifically boric acid (BA) and sodium pentaborate pentahydrate (SPP), which exhibit low toxicity and high bioavailability, and which provides a more effective, safe, and targeted solution compared to conventional methods for the prevention and treatment of tibial dyschondroplasia (TD), a metabolic skeletal disorder commonly observed in broiler chickens.

[0005] PRIOR ART

[0006] Tibial dyschondroplasia (TD) is a prevalent skeletal disorder in broiler chickens characterized by impaired endochondral ossification. TD is associated with multiple biological and molecular factors, including abnormal chondrocyte proliferation and insufficient vascularization, which negatively affect the development of the growth plate (tibial growth plate, TGP) and bone structure in broilers. The disease represents a major health concern in commercial broiler production, leading to significant economic losses and manifesting as leg weakness, impaired walking ability, and bone fractures in broiler flocks. These conditions reduce animal welfare and adversely affect growth performance.

[0007] Among the primary pathological mechanisms of TD is inadequate angiogenesis within the growth plate, resulting in insufficient vascularization of cartilage tissue. This leads to chondrocyte apoptosis and disruption of cartilage matrix mineralization. In the prior art, TD has been reported to negatively affect bone development and cartilage health, potentially causing economic losses of up to 30%. However, due to the often subclinical progression of TD, its prevalence and seventy are frequently underestimated.

[0008] Common strategies employed for the prevention and treatment of TD include mineral and vitamin supplementation, dietary feed additives, and genetic improvement programs. In particular, manganese (Mn) deficiency is considered one of the primary causes of TD. Mn is an essential trace element involved in bone and cartilage development, and its deficiency leads to damage of the tibial growth plate, therebytriggering TD. Existing studies have investigated histopathological and molecular alterations in growth plates of animal models with Mn deficiency-induced TD and have proposed various preventive strategies. Nevertheless, these approaches suffer from several technical limitations. The major problems associated with existing TD prevention and treatment methods include:

[0009] - Insufficient Understanding of Molecular Mechanisms: The pathogenesis of TD is not fully elucidated at the molecular level. Current approaches focus primarily on chondrocyte proliferation, angiogenesis, and osteogenesis, while TD-specific gene expression profiles, signaling pathways, and protein regulation remain inadequately studied, hindering the development of effective treatments.

[0010] - Limited Efficacy of Feed Additives: Existing feed additives, particularly Mn supplementation, demonstrate limited efficacy and do not fully prevent TD associated with Mn deficiency. Determination of optimal dosages and management of potential side effects remain challenging.

[0011] - Limitations of Genetic Interventions: Although selective breeding for TD- resistant broiler lines has been attempted, the widespread application of such strategies is constrained by genetic variability, environmental factors, and high costs. Furthermore, genetic approaches alone cannot fully prevent TD pathogenesis.

[0012] - Side Effects of Pharmacological Approaches: Antioxidants and antiinflammatory agents used in TD treatment may provide short-term benefits but pose risks such as toxicity, drug residues, and adverse effects with long-term use, limiting their applicability in commercial broiler production.

[0013] - Mineral and Vitamin Imbalances: Supplementation with calcium (Ca), phosphorus (P), and vitamin D to support bone mineralization is not always optimally managed. Both deficiencies and excesses may adversely affect bone health and accelerate TD development.

[0014] - Angiogenesis and Vascularization Deficiencies: Angiogenesis plays a critical role in TD pathogenesis but cannot be adequately regulated using existing techniques. Insufficient vascularization in cartilage tissue impairs chondrocyte hypertrophy and endochondral ossification, contributing to TD progression.- Limited Efficacy Duration: While current nutritional and pharmacological interventions offer partial control of TD, their long-term effectiveness is limited, and sustained application often requires costly trials with uncertain outcomes. Accordingly, there remains a need for novel alternative treatment strategies that improve molecular understanding, optimize feed additives and pharmacological approaches, and enhance TD prevention and treatment efficacy.

[0015] BRIEF DESCRIPTION OF THE INVENTION

[0016] The present invention relates to an agent containing boron compounds such as boric acid (BA) and sodium pentaborate pentahydrate (SPP), which exhibit low toxicity and high bioavailability, and which provides a more effective, safe, and targeted solution for the prevention and treatment of tibial dyschondroplasia (TD) in broiler chickens compared to conventional methods. The invention investigates the effects of this agent on the molecular and cellular mechanisms involved in TD pathogenesis, offering a novel feed additive solution for TD prevention, symptom alleviation, and treatment.

[0017] Through the beneficial effects of boron compounds on bone and cartilage tissues, the invention supports skeletal health and reduces the prevalence and seventy of TD. In particular, BA stimulates angiogenesis in the tibial growth plate, enhancing bone mineralization, while SPP promotes osteogenic and chondrogenic differentiation, thereby supporting bone development. Both boron forms exhibit low toxicity and high bioavailability, making them suitable for safe inclusion in poultry diets. The advantages of the invention include:

[0018] - Support of Bone and Cartilage Metabolism: Boron compounds increase bone mineral density and enhance bone strength by improving the absorption of calcium (Ca), phosphorus (P), and magnesium (Mg). Additionally, boron- induced angiogenesis improves vascularization of the growth plate, supporting healthy chondrocyte development. Boron compounds also enhance antioxidant defense systems and reduce inflammatory responses in bone and cartilage tissues, thereby mitigating oxidative stress and inflammation associated with TD.

[0019] - Reduction of Economic Losses: High TD prevalence in broiler operations leads to growth retardation, poor feed conversion, and reduced carcass quality. The present invention improves production efficiency and reduces economiclosses by controlling TD. BA and SPP can be easily incorporated into feed rations and positively influence performance parameters such as body weight, feed efficiency, and carcass yield, while reducing reliance on pharmaceutical treatments and minimizing drug residue risks.

[0020] - Alternative Therapeutic Strategy: In cases where Mn supplementation and genetic selection are insufficient, the boron compound-containing agent of the invention provides an effective alternative approach, particularly for Mn deficiency-induced TD at the molecular level.

[0021] - Improvement of Animal Welfare: By supporting bone and cartilage health, the invention reduces locomotor disorders and bone fractures, thereby improving animal welfare and quality of life.

[0022] - Molecular-Level Effects: The invention demonstrates that boron compounds enhance the expression of proteins regulating osteogenesis and chondrogenesis and stimulate angiogenesis, thereby supporting bone tissue integrity.

[0023] - Evaluation of Different Dosages and Forms: The use of different doses of BA and SPP enables identification of optimal boron forms and dosages for maximum TD prevention efficacy.

[0024] - Prevention of Chronic TD: The long-term protective effects of boron compounds prevent TD chronicity and recurrence, reducing the need for continuous treatment.

[0025] LIST OF FIGURES

[0026] Figure 1. Effects of boron sources [boric acid (BA), sodium pentaborate pentahydrate (SPP)] on bone osteoprotegerin (OPG) (A), receptor activator of nuclear factor kappa-B (RANK) (B), and RANK ligand (RANKL) (C) protein levels in broiler chickens with tibial dyschondroplasia (TD).

[0027] DETAILED DESCRIPTION OF THE INVENTION

[0028] The fundamental steps of the invention are as follows:

[0029] 1. Mn Deficiency-Induced Experimental Model: Tibial dyschondroplasia (TD) is induced in broiler chickens through manganese deficiency, allowing observation of disease pathogenesis and evaluation of therapeutic strategies.Incorporation of Boron Sources into Feed Rations: Experimental groups receive diets supplemented with at least one boron source selected from boric acid (BA) and sodium pentaborate pentahydrate (SPP). BA is administered at ≥25 mg / kg and SPP at ≥26.2 mg / kg, and their effects on bone development and the tibial growth plate are evaluated. The effects of different boron forms on tibial parameters are presented in Tables 1 and 2.

[0030] Evaluation of Bone Metabolism: Bone mineral density and bone structure parameters are assessed following boron supplementation. Osteogenic and chondrogenic protein levels (OPG, RANK, RANKL), as well as serum alkaline phosphatase (ALP), bone alkaline phosphatase (BALP), tartrate-resistant acid phosphatase (TRAP), and osteocalcin (OCN), are analyzed to elucidate molecular mechanisms.Groups Area BMC BMD Growth Width Length (cm2) (g) Plate (mm) (cm)

[0031] (mm)

[0032]

[0033] BA0 8.97±1.16 2.53±0.30 0.28±0.04 1.89±0.18 7.33±0.67 9.92±0.50 BA1 9.15±0.91 2.69±0.26 0.29±0.02 1.9±0.10 7.48±0.66 10.26±0.85 BA2 9.34±1.19 2.72±0.28 0.32±0.03 1.97±0.18 7.54±0.45 10.26±0.90 SPP0 8.98±0.91 2.52±0.33 0.28±0.03 1.87±0.32 7.56±0.42 10.33±0.65 SPP1 9.32±0.57 2.86±0.49 0.32±0.04 2.00±0.26 7.72±0.79 10.47±0.79 SPP2 9.59±0.74 3.02±0.47 0.33±0.04 2.03±0.20 7.97±0.58 10.48±0.74 TD+BA0 8.02±1.08 2.25±0.38 0.24±0.05 1.73±0.17 6.99±0.40 9.72±0.89 TD+BA1 8.83±1.16 2.46±0.38 0.26±0.04 1.81±0.20 7.32±0.31 9.89±0.53 TD+BA2 8.88±1.15 2.58±0.55 0.29±0.03 1.83±0.23 7.46±0.24 9.84±0.96 TD+SPP0 8.74±1.11 2.21±0.64 0.26±0.05 1.72±0.31 7.17±0.30 9.62±0.39 TD+SPP1 8.90±0.94 2.56±0.19 0.27±0.03 1.86±0.27 7.45±0.56 10.16±0.37 TD+SPP2 9.07±0.82 2.77±0.45 0.31±0.02 1.89±0.35 7.47±0.75 10.32±0.73 p values

[0034] TD Status 0.004 0.001 0.001 0.001 0.002 0.003 Boron Source 0.161 0.09 0.007 0.322 0.026 0.041 Boron Dose 0.027 0.001 0.001 0.036 0.007 0.048 ID States*B®ron

[0035] 0.607 0.591 0.928 0.808 0.288 0.797 Source

[0036] TD States* Boron

[0037] 0.725 0.817 0.918 0.903 0.787 0.847 Dose

[0038] Boron

[0039] 0.786 0.28 0.793 0.673 0.985 0.807 Souroe*Boron Dose

[0040] TD Sta.tes*Boron

[0041] 0.559 0.967 0.593 0.946 0.656 0.395 Source*: Boron Dose

[0042] Linear Contrast 0.009 0.001 0.001 0.012 0.002 0.026 Quadratic Contrast 0.558 0.377 0.512 0.551 0.562 0.29

[0043] Table 1. Effects of different boron forms on tibial bone parameters - 1Groups ALP BALB TRAP OCN (ng / ml) (ng / ml)

[0044]

[0045] BA0 89.9±3.88 10.38±0.99 5.13±0.25 56.96±4.12a BA1 90.07±6.13 9.95±1.02 5.16±0.47 57.93±4.09a BA2 90.39±7.21 10.19±0.93 5.07±0.56 57.64±3.86a SPP0 92.64±4.70 10.25±0.62 5.20±0.29 58.91±5.11a SPP1 92.36±7.89 10.10±0.86 5.15±0.33 56.77±4.65a SPP2 90.76±5.35 10.44±0.84 5.04±0.19 54.93±4.05a TD+BA0 131.8±7.77 5.89±0.45 8.62±0.32 33.11±3.09e TD+BA1 119.02±9.59 6.40±0.58 8.21±0.29 37.60±4.49cde TD+BA2 108.73±5.86 6.70±0.48 7.89±0.48 39.98±5.70cd TD+SPP0 135.83±9.98 5.77±0.32 8.53±0.47 34.64±3.09de TD+SPP1 116.74±9.41 6.62±0.66 8.31±0.60 42.35±3.42bc TD+SPP2 101.24±7.37 7.11±0.37 7.74±0.60 48.25±3.92b p values

[0046] TD Status 0.001 0.001 0.001 0.001 Boron Source 0.072 0.324 0.831 0.007 Boron Dose 0.001 0.004 0.001 0.001 TD Status * Boron Source 0.635 0.773 0.701 0.001 TD Status * Boron Dose 0.001 0.002 0.004 0.001 Bor Kaynağı* Boron Dose 0.419 0.343 0.764 0.824 TD Status*Boron 0.235 0.969 0.756 0.012 Source*Boron Dose

[0047] Linear Contrast 0.001 0.001 0.001 0.001 Quadratic Contrast 0.665 0.591 0.503 0.456

[0048] Table 2. Effects of different boron forms on tibial bone parameters - 2The contents of the groups are listed below:

[0049] 1. BAO: Basal diet without BA

[0050] 2. BA1: Basal diet + 25 mg / kg BA (1.43 mg / kg elemental boron)

[0051] 3. BA2: Basal diet + 50 mg / kg BA (2.86 mg / kg elemental boron)

[0052] 4. SPPO: Basal diet without SPP

[0053] 5. SPP1: Basal diet + 26.2 mg / kg SPP (1.43 mg / kg elemental boron)

[0054] 6. SPP2: Basal diet + 52.4 mg / kg SPP (2.86 mg / kg elemental boron)

[0055] 7. TD+BAO: Basal diet with 22 mg / kg Mn, without BA

[0056] 8. TD+BA1: Basal diet with 22 mg / kg Mn + 25 mg / kg BA (1.43 mg / kg elemental boron)

[0057] 9. TD+BA2: Basal diet with 22 mg / kg Mn + 50 mg / kg BA (2.86 mg / kg elemental boron)

[0058] 10. TD+SPP0: Basal diet with 22 mg / kg Mn, without SPP

[0059] 11. TD+SPP1: Basal diet with 22 mg / kg Mn + 26.2 mg / kg SPP (1.43 mg / kg elemental boron)

[0060] 12. TD+SPP2: Basal diet with 22 mg / kg Mn + 52.4 mg / kg SPP (2.86 mg / kg elemental boron)

Claims

CLAIMS1. An agent for the prevention and treatment of tibial dyschondroplasia (TD) in broiler chickens, providing an effective, safe, and targeted solution with low toxicity and high bioavailability, characterized by; containing at least one boron compound selected from boric acid (BA) and sodium pentaborate pentahydrate (SPP) at least 1.43 mg / kg elemental boron.

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